Coronavirus vaccines and methods of use

Abstract

Compositions and methods for the prevention and / or treatment of a viral infection, in particular of the Coronaviridae family.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. U.S. 63 / 246,902 filed Sep. 22, 2021, and U.S. Provisional Application No. 63 / 320,187 filed Mar. 15, 2022, the content of each of which is hereby incorporated herein in its entirety.BACKGROUND

[0002] Newly emerging acute respiratory virus infections caused by novel coronavirus is a significant public health concern. Importantly, there are no vaccines or specific antivirals at the time of an outbreak, specifically, for example the MERS-CoV of 2015, or 2019 SARS CoV-2 infections. The 2019 SARS COV-2 infection outbreak in December of 2019 claimed more than 2000 lives in less than 2 months from the first reported case. Accordingly, novel and easily scalable therapeutics are necessary to combat a disease caused by such a viral infection.

[0003] The present application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML file copy, created on Sep. 15, 2025, is named 2013237-0996.xml and is 23,117,867 bytes in size.SUMMARY

[0004] Patients who are immunocompromised because of autoimmunity, organ transplant or immunosuppressive treatment have reduced ability to produce antibody responses to vaccinations (Rousseau et al., A H1N1v 2009 vaccine in cancer patients treated with cytotoxic chemotherapy and / or targeted therapy: the VACANCE study. Ann Oncol. 2012 February;23 (2): 450-7). Seropositivity after vaccination is decreased in immunocompromised patients (Haidar et al., Immunogenicity of COVID-19 Vaccination in Immunocompromised Patients: An Observational, Prospective Cohort Study Interim Analysis. medRxiv 2021.06.28.21259576). While immunocompromised patients were excluded from the original clinical trials testing current SARS-CoV-2 vaccines targeting spike protein, follow-up analysis of immunocompromised patients have shown reduced capacity for patients to mount broad and durable anti-spike antibody responses, particularly in older patient cohorts (Boyarsky, et al., Immunogenicity of a Single Dose of SARS-CoV-2 Messenger RNA Vaccine in Solid Organ Transplant Recipients. JAMA. 2021; 325 (17): 1784-1786; Rincon-Arevalo, et al., Impaired antigen-specific memory B cell and plasma cell responses including lack of specific IgG upon SARS-CoV-2 BNT162b2 vaccination among Kidney Transplant and Dialysis patients. medRxiv 2021.04.15.21255550). Thus, induction of T cell responses to other SARS-CoV-2 viral proteins may be beneficial to enhance both cellular and humoral immunity. Thus, there is a need for a SARS-CoV-2 vaccine that specifically targets T cell responses. Patients undergoing anti-CD20 treatment were shown to be able to develop functional T cells with vaccination (Apostolidis et al., Altered cellular and humoral immune responses following SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis on anti-CD20 therapy. Nature Medicine, vol. 27, pp. 1990-2001 (2021)), indicating that patients with impaired B cells may still develop SARS-CoV 2-specific T cells in response to vaccination.

[0005] Provided herein is an immunogenic composition (e.g., a vaccine) that specifically targets one or more T cell responses to a pathogen (e.g., in some embodiments a virus), including CD4+ T cell responses and / or CD8+ T cell responses, and / or leverages long term persistence of T cell immunity. In some embodiments, an immunogenic composition (e.g., vaccine) provided herein can specifically target one or more T cell responses to one or more polypeptide antigens of a pathogen (e.g., in some embodiments one or more viral antigens), including, e.g., non-structural proteins, nucleocapsid, membrane protein and / or envelope protein of one or more viruses.

[0006] In one aspect, provided herein is a SARS-CoV-2 immunogenic composition (e.g., a vaccine) that specifically targets one or more T cell responses, including CD4+ T cell responses and / or CD8+ T cell responses, and / or leverages long term persistence of T cell immunity. In some embodiments, a SARS-CoV-2 vaccine provided herein can specifically target one or more T cell responses to a polypeptide antigen of SARS-CoV-2, including, e.g., nucleocapsid, membrane protein and / or envelope protein of SARS-CoV-2. SARS-CoV-2 immunogenic compositions (e.g., a vaccines) provided herein can be useful for eliciting one or more T cell responses to SARS-CoV-2 in all patients. Protection from COVID19 has been observed in patients deficient in humoral immunity when T cell responses were present (Bange, et al., CD8+ T cells contribute to survival in patients with COVID-19 and hematologic cancer. Nat Med 27, 1280-1289 (2021)) and the longevity of T cell responses from related infections from the original SARS-CoV epidemic (Le Bert et al., SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature 584, 457-462 (2020)). In some embodiments, the present disclosure, among other things, provides a particular insight that SARS-CoV-2 immunogenic compositions (e.g., a vaccines) provided herein can be particularly useful for eliciting one or more T cell responses to SARS-CoV-2 in patients that have been immunocompromised in their humoral immunity, such as, for example, in some embodiments through cancer (e.g., B cell lymphoma), treatment with rituximab, methotrexate or other immunosuppressive treatment targeting the humoral immune response, or patients undergoing organ transplant. In some embodiments, T cell responses induced by SARS-CoV-2 immunogenic compositions (e.g., a vaccines) described herein can protect patients from severe COVID-19 and provide long lasting protection through T cell immunity to the SARS-CoV-2 immunogenic composition (e.g., a vaccine) provided herein. Additionally or alternatively, in some embodiments, SARS-CoV-2 immunogenic compositions (e.g., a vaccines) provided herein can be used to overcome SARS-CoV-2 variants that could reduce efficacy of other vaccines, such as those that do not target T cell responses (Davis et al., Reduced neutralisation of the Delta (B.1.617.2) SARS-CoV-2 variant of concern following vaccination. PLoS Pathog., 17 (12): e1010022 (2021); Tada et al., Comparison of Neutralizing Antibody Titers Elicited by mRNA and Adenoviral Vector Vaccine against SARS-CoV-2 Variants. bioRxiv 2021.07.19.452771). In some embodiments, the immunogenic compositions described herein are used to treat a subject with SARS-CoV-2B1.1.529 (omicron) variant or to immunize a subject against SARS-CoV-2 B1.1.529 (omicron) variant. In some embodiments, SARS-CoV-2 immunogenic compositions (e.g., a vaccines) provided herein can be used to complement and / or enhance other immunogenic compositions (e.g., a vaccines), such as those that do not target T cell responses. For example, in some embodiments, SARS-CoV-2 immunogenic compositions (e.g., a vaccines) provided herein can be used to enhance B cell responses through increased CD4+ T cell activation.

[0007] Coronaviruses are single positive stranded RNA viruses that have emerged occasionally from zoonotic sources to infect human populations. Most of the infections in humans cause mild respiratory symptoms, though some recent coronavirus infections in the last decade have resulted in severe morbidity and mortality. These include the severe acute respiratory syndrome coronavirus (SARS-CoV), middle east respiratory syndrome coronavirus (MERS-CoV) and the currently ongoing pandemic of SARS-CoV-2. Infection with these viruses can lead to acute respiratory distress resulting in a high mortality rate. SARS-CoV originated in 2002 in South China and its global spread led to 8096 cases and 774 deaths. The first case of MERS-CoV emerged in 2012 in Saudi Arabia and since then a total of 2494 cases and 858 associated deaths have been reported. 2019 SARS CoV-2 emerged in Wuhan, China at the end of December 2019 and by Mar. 8, 2020 had resulted in 118,096 cases including 4262 deaths globally. The rapid spread of 2019 SARS-CoV-2 resulted in the World Health Organization declaring a global pandemic of international concern.

[0008] All three coronaviruses SARS-CoV, MERS-CoV and the recently emergent SARS CoV-2 belong to the genus beta coronaviridae. SARS CoV-2 has a genome size of 30 kilobases that encodes for at least four (4) structural (spike [S], envelope [E], membrane [M], and nucleocapsid [N]) and at least sixteen (16) non-structural (NSP 1-16) proteins. S protein facilitates viral entry into target cells and entry depends on binding of the spike protein to a cellular receptor ACE2 for both SARS-CoV and SARS-CoV-2. Both viruses share a 76% amino acid identity across the genome.

[0009] The field of the present disclosure relates to immunotherapeutic peptides, nucleic acids encoding the peptides, peptide binding agents, and their use, for example, in the immunotherapy of a viral disease. In one aspect, the present disclosure provides viral epitopes expressed in virus infected cells, useful alone or in combination with other anti-viral, or immunomodulatory agents to treat viral infection. The present disclosure is useful in immunotherapy for a coronavirus infection.

[0010] Provided herein is a method of treating or preventing an infection by a virus (e.g., SARS-CoV-2) or treating a respiratory disease or condition associated with an infection by a virus (e.g., SARS-CoV-2) comprising administering to a subject with a B cell immunodeficiency a pharmaceutical composition comprising: (i) a polypeptide comprising at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, (b) a sequence comprising an epitope sequence from membrane glycoprotein (M) and (c) a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); (ii) a polynucleotide encoding a polypeptide, wherein the polypeptide comprises at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, (b) a sequence comprising an epitope sequence from membrane glycoprotein (M) and (c) a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); (iii) a T cell receptor (TCR) or a T cell comprising the TCR, wherein the TCR binds to an epitope sequence of the polypeptide in complex with a corresponding HLA class I or class II molecule; (iv) an antigen presenting cell comprising (i) or (ii); or (v) an antibody or B cell comprising the antibody, wherein the antibody binds to an epitope sequence of the polypeptide.

[0011] In some embodiments, the subject has a reduced ability to produce an antibody response to an antigen compared to a subject without a B cell immunodeficiency.

[0012] In some embodiments, the subject has a reduced ability to produce an antibody response to a vaccination compared to a subject without a B cell immunodeficiency.

[0013] In some embodiments, the subject has a reduced ability to produce an anti-spike protein antibody response and / or an anti-RBD antibody response compared to a subject without a B cell immunodeficiency.

[0014] In some embodiments, the subject can produce a T cell response or does not have a reduced ability to produce a T cell response compared to a subject without a B cell immunodeficiency.

[0015] In some embodiments, the pharmaceutical composition is protective against a variant of 2019 SARS CoV-2.

[0016] In some embodiments, the variant of 2019 SARS CoV-2 is alpha, beta, gamma, delta, epsilon, zeta, eta, theta, iota, kappa or lambda.

[0017] In some embodiments, the subject produces a T cell response to an epitope of the polypeptide.

[0018] In some embodiments, the subject produces a T cell response to the epitope sequence from ORF1ab, the epitope sequence from membrane glycoprotein (M) and / or the epitope sequence from nucleocapsid phosphoprotein (N).

[0019] In some embodiments, the subject is an organ transplant recipient.

[0020] In some embodiments, the organ transplant recipient is a sold organ transplant recipient, a stem cell transplant recipient or a bone marrow transplant recipient.

[0021] In some embodiments, the subject received an organ transplant less than 1 year, less than 6 months or less than 3 months after the pharmaceutical composition is administered.

[0022] In some embodiments, the subject is expected to receive an organ transplant less than 1 year, less than 6 months or less than 3 months prior to the pharmaceutical composition being administered.

[0023] In some embodiments, the subject has a cancer.

[0024] In some embodiments, the cancer is a B cell cancer.

[0025] In some embodiments, the B cell cancer is a B cell lymphoma or a B cell leukemia.

[0026] In some embodiments, the subject has an autoimmune disease or condition.

[0027] In some embodiments, the autoimmune disease or condition is Addison disease, Anti-NMDA receptor encephalitis, antisynthetase syndrome, Aplastic anemia, autoimmune anemias, Autoimmune hemolytic anemia, Autoimmune pancreatitis, Behcet's Disease, bullous skin disorders, Celiac disease-sprue, chronic fatigue syndrome, Chronic inflammatory demyelinating polyneuropathy, chronic lymphocytic leukemia, Crohn's disease, Dermatomyositis, Devic's disease, Erythroblastopenia, Evans syndrome, Focal segmental glomerulosclerosis, Granulomatosis with polyangiitis, Graves disease, Graves' ophthalmopathy, Guillain-Barre syndrome, Hashimoto thyroiditis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, IgA-mediated autoimmune diseases, IgG4-related disease, Inflammatory bowel disease, Juvenile idiopathic arthritis, Multiple sclerosis, Myasthenia gravis, myeloma, non-Hodgkin's lymphoma, Opsoclonus myoclonus syndrome (OMS), Pemphigoid, Pemphigus, pemphigus vulgaris, Pernicious anemia, polymyositis, Psoriasis, pure red cell aplasia, Reactive arthritis, Rheumatoid arthritis, Sarcoidosis, scleroderma, Sjögren syndrome, Systemic lupus erythematosus, Thrombocytopenia purpura, Thrombotic thrombocytopenia purpura, Type I diabetes, Ulcerative colitis, Vasculitis and Vitiligo.

[0028] In some embodiments, the subject does not have congenital agammaglobulinemia or congenital IgA deficiency.

[0029] In some embodiments, the subject does not have HIV or AIDS.

[0030] In some embodiments, the subject is receiving an immunosuppressive agent or has received an immunosuppressive agent less than 1 year, less than 6 months or less than 3 months prior to the administering of the pharmaceutical composition.

[0031] In some embodiments, the immunosuppressive agent is abatacept, abrilumab, acalabrutinib, adalimumab, adrenocorticotropic hormone, agatolimod sodium, aldesleukin, alefacept, alemtuzumab, alisertib, alvespimycin hydrochloride, alvocidib, ambrisentan, aminocamptothecin, amiselimod, anakinra, andecaliximab, andrographolides, anifrolumab, antithymocyte Ig, apatinib, apelisib, asparaginase, atacicept, atezolizumab, avelumab, azacitidine, azathioprine, bafetinib, baminercept, baricitinib, basiliximab, becatecarin, begelomab, belatacept, belimumab, bemcentinib, bendamustine, bendamustine, betalutin with lilotomab, bevacizumab, BIIB033, BIIB059, BIIB061, bimekizumab, binimetinib, bleomycin, blinatumomab, bortezomib, brentuximab vedotin, bryostatin 1, bucillamine, buparlisib, busulfan, canakinumab, capecitabine, carboplatin, carfilzomib, carmustine, cediranib maleate, cemiplimab, ceralifimod, cerdulatinib, certolizumab, cetuximab, chidamide, chlorambucil, cilengitide, cirmtuzumab, cisplatin, cladribine, clazakizumab, clemastine, clioquinol, corticosteroids, cyclophosphamide, cyclosporine, cytarabine, cytotoxic chemotherapy, daclizumab, dalfampridine, daprolizumab pegol, daratumumab, dasatinib, defactinib, defibrotide, denosumab, dexamethasone, diacerein, dimethyl fumarate, dinaciclib, diroximel fumarate, doxorubicin, doxorubicin, durvalumab, duvelisib, duvortuxizumab, eculizumab, efalizumab, eftilagimod alpha, a neuropeptide combination of metenkefalin and tridecactide, elezanumab, elotuzumab, encorafenib, enfuvirtida, entinostat, entospletinib, enzastaurin, epacadostat, epirubicin, epratuzumab, eritoran tetrasodium, etanercept, etoposide, etrolizumab, everolimus, evobrutinib, filgotinib, fingolimod, firategrast, fludarabine, fluorouracil, fontolizumab, forodesine hydrochloride, fostamatinib, galunisertib, ganetespib, ganitumab, gemcitabine, gemtuzumab ozogamicin, gerilimzumab, glasdegib, glassia, glatiramer acetate, glembatumumab vedotin, glesatinib, golimumab, guadecitabine, hydrocortisone, hydroxychloroquine sulfate, hydroxyurea, ibritumomab tiuxetan, ibrutinib, ibudilast, idarubicin, idebenone, idelalisib, ifosfamide, iguratimod, imatinib, imexon, infliximab, inotuzumab ozogamicin, interferon alfa-2, interferon beta-la, interferon beta-1b, interferon gamma-1, ipilimumab, irofulven, isatuximab, ispinesib, itacitinib, ixazomib, lapatinib, laquinimod, laromustine, ld-aminopterin, leflunomide, lenalidomide, lenvatinib, letrozole, levamisole, levocabastine, lipoic acid, lirilumab, lonafarnib, lumiliximab, maraviroc, masitinib, mavrilimumab, melphalan, mercaptopurine, methotrexate, methoxsalen, methylprednisone, milatuzumab, mitoxantrone, mizoribine, mocetinostat, monalizumab, mosunetuzumab, motesanib diphosphate, moxetumomab pasudotox, muromonab-CD3, mycophenolate mofetil, mycophenolic acid, namilumab, natalizumab, navitoclax, neihulizumab, nerispirdine, neurovax, niraparib, nivolumab, obatoclax mesylate, obinutuzumab, oblimersen sodium, ocrelizumab, ofatumumab, olokizumab, opicinumab, oprelvekin, osimertinib, otelixizumab, oxaliplatin, oxcarbazepine, ozanimod, paclitaxel, pacritinib, palifermin, panobinostat, pazopanib, peficitinib, pegfilgrastim, peginterferon beta-la, pegsunercept (peg stnf-ri), pembrolizumab, pemetrexed, penclomedine, pentostatin, perifosine, pevonedistat, pexidartinib, picoplatin, pidilizumab, pivanex, pixantrone, pleneva, plovamer acetate, polatuzumab vedotin, pomalidomide, ponatinib, ponesimod, prednisone / prednisolone, pyroxamide, ravulizimab-cwvz, recombinant il-12, relatlimab, rhigf-1, rhigm22, rigosertib, rilonacept, ritonavir, rituximab, ruxolitinib, sarilumab, secukinumab, selumetinib, simvastatin, sintilimab, siplizumab, siponimod, sirolimus (rapamycin), sirukumab, sitravatinib, sonidegib, sorafenib, sotrastaurin acetate, sunitinib, sunphenon epigallocatechin-gallate, tabalumab, tacrolimus, talabostat mesylate, talacotuzumab, tanespimycin, tegafur / gimeracil / oteracil, temozolomide, temsirolimus, tenalisib, terameprocol, teriflunomide, thalidomide, thiarabine, thiotepa, tipifarnib, tirabrutinib, tislelizumab, tivozanib, tocilizumab, tofacitinib, tregalizumab, tremelimumab, treosulfan, ublituximab, umbralisib, upadacitinib, urelumab, ustekinumab, varlilumab, vatelizumab, vedolizumab, veliparib, veltuzumab, venetoclax, vinblastine, vincristine, vinorelbine ditartrate, visilizumab, vismodegib, vistusertib, voriconazole, vorinostat, vosaroxin, ziv-aflibercept or any combination thereof.

[0032] In some embodiments, the immunosuppressive agent is A2aR antagonist, Akt inhibitor, anti CD20, Anti-amyloidotic (AA) Agent, anti-CD37 protein therapeutic, anti-CTLA4 mAb, Anti-CXCR4, anti-huCD40 mAb, anti-LAG3 mAb, anti-PD-1 mAb, anti-PD-L1 agent, anti-PD-L1 agent, anti-PD-L1 mAb, anti-TGFb mAb, anti-TIGIT mAb, anti-TIM-3 mAb, Aurora kinase inhibitor, Bcl-2 Inhibitor, bifunctional fusion protein targeting TGFb and PD-L1, bispecific anti-PD-1 and anti-LAG3 mAb, CD1d ligand, CD40 agonist, Complement C5a inhibitor, CSF1R inhibitor, EZH2 inhibitor, FGFR3 inhibitor, FGFR4 inhibitor, FGFrR3 inhibitor, glucocorticoid-induced tumor necrosis factor receptor-related gene agonist, glutaminase inhibitor, Human monoclonal antibody against IL-12, ICOS agonist, IDO1 inhibitor, IL2 mutein, IL2 receptor agonist, MEK inhibitor, multitargeted receptor tyrosine kinase inhibitor, neutrophil elastase inhibitor, Notch Inhibitor, p38 MAPK inhibitor, PD-1 inhibitor, recombinant human Flt3L, ROCK inhibitor, selective sphingosine-1-phosphate receptor modulator, Src kinase inhibitor, TLR4 agonist, TLR9 agonist, or any combination thereof.

[0033] In some embodiments, the subject is greater than 55, 56, 57, 58, 59, 60, 65, 70, 75 or 80 years of age.

[0034] In some embodiments, the polypeptide comprises (a) a sequence comprising an epitope sequence from ORF1ab, (b) a sequence comprising an epitope sequence from membrane glycoprotein (M) and (c) a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N).

[0035] In some embodiments, the sequence comprising an epitope sequence from ORF1ab is C-terminal to the sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N).

[0036] In some embodiments, the sequence comprising an epitope sequence from ORF1ab is N-terminal to the sequence comprising an epitope sequence from membrane glycoprotein (M).

[0037] In some embodiments, the sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N) is N-terminal to the sequence comprising an epitope sequence from membrane glycoprotein (M).

[0038] In some embodiments, the polypeptide comprises (a) 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more epitope sequences from ORF1ab, (b) a sequence comprising an epitope sequence from membrane glycoprotein (M) and (c) a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N).

[0039] In some embodiments, the epitope sequence from ORF1ab is an epitope sequence from a non-structural protein (NSP).

[0040] In some embodiments, the non-structural protein (NSP) is selected from the group consisting of NSP1, NSP2, NSP3, NSP4 and combinations thereof.

[0041] In some embodiments, the polypeptide comprises a sequence comprising an epitope sequence from NSP1, a sequence comprising an epitope sequence from NSP2, a sequence comprising an epitope sequence from NSP3 and a sequence comprising an epitope sequence from NSP4.

[0042] In some embodiments, the epitope sequence from ORF1ab is selected from the group consisting of YLFDESGEFKL, YLFDESGEF, FGDDTVIEV, QLMCQPILL, TTDPSFLGRY, PTDNYITTY, PSFLGRY, AEAELAKNV, KTIQPRVEK and any combination thereof.

[0043] In some embodiments, the epitope sequence from nucleocapsid glycoprotein (N) is LLLDRLNQL.

[0044] In some embodiments, the epitope sequence from membrane phosphoprotein (M) is VATSRTLSY.

[0045] In some embodiments, the polypeptide comprises an epitope sequence from nucleocapsid glycoprotein (N) that is LLLDRLNQL and an epitope sequence from membrane phosphoprotein (M) that is VATSRTLSY.

[0046] In some embodiments, the polypeptide comprises (a) each of the following epitope sequences from ORF1ab: YLFDESGEFKL, YLFDESGEF, FGDDTVIEV, QLMCQPILL, TTDPSFLGRY, PTDNYITTY, PSFLGRY, AEAELAKNV, KTIQPRVEK; (b) an epitope sequence from nucleocapsid glycoprotein (N) that is LLLDRLNQL; and (c) an epitope sequence from membrane phosphoprotein (M) that is VATSRTLSY.

[0047] In some embodiments, the sequence comprising an epitope sequence from ORF1ab is selected from the group consisting of the following sequences or fragments thereof:MVTNNTFTLKVPHVGEIPVAYRKVLLKTIQPRVEKYLFDESGEFKLSEVGPEHSLAEYYIFFASFYY; MVTNNTFTLKVPHVGEIPVAYRKVLLKTIQPRVEKYLFDESGEFKLSEVGPEHSLAEY; APKEIIFLEGETLFGDDTVIEVAIILASFSAST; APKEIIFLEGETLFGDDTVIEV; HTTDPSFLGRYMSALFADDLNQLTGYHTDFSSEIIGYQLMCQPILLAEAELAKNVSLILGTVSWNL; TTDPSFLGRYMSALFADDLNQLTGYHTDFSSEIIGYQLMCQPILLAEAELAKNVSLILGTVSWNL; LLSAGIFGAITDVFYKENSYKVPTDNYITTY; and combinations thereof.

[0048] In some embodiments, the sequence comprising an epitope sequence from membrane glycoprotein (M) is selected from the group consisting of the following sequences or fragments thereof:ADSNGTITVEELKKLLEQWNLVIGFLFLTWICLLQFAYANRNRFLYIIKLIFLWLLWPVTLACFVLAAVYRINWITGGIAIAMACLVGLMWLSYFIASFRLFARTRSMWSFNPETNILLNVPLHGTILTRPLLESELVIGAVILRGHLRIAGHHLGRCDIKDLPKEITVATSRTLSYYKLGASQRVAGDSGFAAYSRYRIGNYKLNTDHSSSSDNIALLVQ; FAYANRNRFLYIIKLIFLWLLWPVTLACFVLAAVYRINWITGGIAIAMACLVGLMWLSYFIASFRLF; LGRCDIKDLPKEITVATSRTLSYYKLGASQRVA; KLLEQWNLVIGF; NRNRFLYII KLIFLWLLWPVTLACFVLAAVY; SELVIGAVILRGHLRIAGHHLGR; VATSRTLSYYKLGASQRV; GLMWLSYF; and combinations  thereof.

[0049] In some embodiments, the sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N) is selected from the group consisting of the following sequences or fragments thereof:KDLSPRWYFYYLGTGPEAGLPYGANKDGIIWVATEGALNTPKDHIGTRNPANNAAIVLQLPQGTTLPKGFYAEGSRGGSQASSRSSSRSRNSSRNSTPGSSRGTSPARMAGNGGDAALALLLLDRLNQLESKMSGKGQQQQGQTVTKKSAAEASKKPRQKRTATKAYNVTQAFGRRGPEQTQGNFGDQELIRQGTDYKHWPQIAQFAPSASAFFGMSRIGMEVTPSGTWLTYTGAIKLDDKDPNFKDQVILLNKHIDAYKTFPPTEPKKDKKKKADETQALPQRQKKQQTVTLLPAADLDDFSKQLQQSMSSADSTQA; RMAGNGGDAALALLLLDRLNQLESKMSGKGQQQ; YKHWPQIAQFAPSASAFFGMSRIGMEVTPSGTWLTYTGAIKLDDKDPNFKDQVILLNKHIDAYKTFP; SPARMAGNGGDAALALLLLDRLNQLESKMSGKGQQQQGQTVTKKSAAEASKKPRQKRTATKAYNVTQAFGRRGPEQTQGNFGDQELIRQGTDYKHWPQIAQFAPSASAFFGMSRIGMEVTPSGTWLTYTGAIKLDDKDPNFKDQVILLNKHIDAYKTFPPTEPKKDK and combinations thereof.

[0050] In some embodiments, the polypeptide comprises one or more linker sequences.

[0051] In some embodiments, the one or more linker sequences are selected from the group consisting of GGSGGGGSGG, GGSLGGGGSG.

[0052] In some embodiments, the one or more linker sequences comprise cleavage sequences.

[0053] In some embodiments, the one or more cleavage sequences are selected from the group consisting of FRAC, KRCF, KKRY, ARMA, RRSG, MRAC, KMCG, ARCA, KKQG, YRSY, SFMN, FKAA, KRNG, YNSF, KKNG, RRRG, KRYS, and ARYA.

[0054] In some embodiments, the polypeptide comprises a transmembrane domain sequence.

[0055] In some embodiments, the transmembrane domain sequence is C-terminal to the sequence comprising an epitope sequence from ORF1ab, the sequence comprising an epitope sequence from membrane glycoprotein (M) and the sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N).

[0056] In some embodiments, the transmembrane domain sequence is EQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKL HYT.

[0057] In some embodiments, the polypeptide comprises an SEC sequence.

[0058] In some embodiments, the SEC sequence is N-terminal to the sequence comprising an epitope sequence from ORF1ab, the sequence comprising an epitope sequence from membrane glycoprotein (M) and the sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N).

[0059] In some embodiments, the SEC sequence is MFVFLVLLPLVSSQCVNLT.

[0060] In some embodiments, the composition comprises the polynucleotide encoding the polypeptide.

[0061] In some embodiments, the polynucleotide is an mRNA.

[0062] In some embodiments, the polynucleotide comprises a codon optimized sequence for expression in a human.

[0063] In some embodiments, the polynucleotide comprises a dEarI-hAg sequence.

[0064] In some embodiments, the dEarI-hAg sequence is ATTCTTCTGGTCCCCACAGACTCAGAGAGAACCC, optionally wherein each T is a U.

[0065] In some embodiments, the polynucleotide comprises a Kozak sequence.

[0066] In some embodiments, the Kozak sequence is GCCACC.

[0067] In some embodiments, the polynucleotide comprises an F element sequence.

[0068] In some embodiments, the F element sequence is a 3 UTR of amino-terminal enhancer of split (AES).

[0069] In some embodiments, the F element sequence is CTGGTACTGCATGCACGCAATGCTAGCTGCCCCTTTCCCGTCCTGGGTACCCCGAGTCTCCC CCGACCTCGGGTCCCAGGTATGCTCCCACCTCCACCTGCCCCACTCACCACCTCTGCTAGTTC CAGACACCTCC, optionally wherein each T is a U.

[0070] In some embodiments, the polynucleotide comprises an I element sequence.

[0071] In some embodiments, the I element sequence is a 3′ UTR of mitochondrially encoded 12S rRNA (mtRNR1).

[0072] In some embodiments, the I element sequence is CAAGCACGCAGCAATGCAGCTCAAAACGCTTAGCCTAGCCACACCCCCACGGGAAACAGCA GTGATTAACCTTTAGCAATAAACGAAAGTTTAACTAAGCTATACTAACCCCAGGGTTGGTCA ATTTCGTGCCAGCCACACC, optionally wherein each T is a U.

[0073] In some embodiments, the polynucleotide comprises a poly A sequence.

[0074] In some embodiments, the poly A sequence is AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAGCATATGACTAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA, optionally wherein each T is a U.

[0075] In some embodiments, each of the epitope sequences from the ORF1ab, the membrane glycoprotein, and the nucleocapsid phosphoprotein are from 2019 SARS-CoV-2.

[0076] In some embodiments, one or more or each epitope elicits a T cell response.

[0077] In some embodiments, one or more or each epitope has been observed by mass spectrometry as being presented by an HLA molecule.

[0078] In some embodiments, the composition comprises (i) a polypeptide with at least 70%, at least 75%, at least 80%, at least 85%, 90%, at least 95%, or 100% sequence identity to a sequence selected from the group consisting of RS Clp1full, RS C2p1full, RS C3p1full, RS C4p1full, RS C5p1, RS C5p2, RS C5p2full, RS C6p1, RS C6p2, RS C6p2full, RS C7p1, RS C7p2, RS C7p2full, RS C7p4, RS C7p4full, RS C8p1, RS C8p2 and RS C8p2full; (ii) a polynucleotide encoding a polypeptide with at least 70%, at least 75%, at least 80%, at least 85%, 90%, at least 95%, or 100% sequence identity to a sequence selected from the group consisting of RS Clp1full, RS C2p1full, RS C3p1full, RS C4p1full, RS C5p1, RS C5p2, RS C5p2full, RS C6p1, RS C6p2, RS C6p2full, RS C7p1, RS C7p2, RS C7p2full, RS C7p4, RS C7p4full, RS C8p1, RS C8p2 and RS C8p2full; or (iii) a polynucleotide with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: RS C1n1, RS C2n1, RS C3n1, RS C4n1, RS C5n1, RS Con1, RS C7n1, RS C8n1, RS C5n2, RS Con2, RS C7n2, RS C7n4, RS C7n4full, RS C8n2, RS C5n2full, RS Con2full, RS C7n2full and RS C8n2full.

[0079] In some embodiments, the composition comprises (i) a polypeptide with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence selected from the group consisting of RS C7p1, RS C7p2, RS C7p2full, RS C7p4 and RS C7p4full; or (ii) a polynucleotide with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: RS C7n1, RS C7n2, RS C7n2full, RS C7n4 and RS C7n4full.

[0080] In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient, carrier, or diluent.

[0081] Provided herein is a method of treating or preventing an infection by a virus or treating a respiratory disease or condition associated with an infection by a virus comprising administering to a subject with a B cell immunodeficiency a pharmaceutical composition comprising: (i) a polypeptide comprising an epitope sequence of Table 1A, Table 1B, Table 1C, Table 2Ai, Table 2Aii, Table 2B and / or Table 16; (ii) a polynucleotide encoding the polypeptide comprising an epitope sequence of Table 1A, Table 1B, Table 1C, Table 2Ai, Table 2Aii, Table 2B and / or Table 16; (iii) a T cell receptor (TCR) or a T cell comprising the TCR, wherein the TCR binds to the epitope sequence in complex with a corresponding HLA class I or class II molecule; (iv) an antigen presenting cell comprising (i) or (ii); or (v) an antibody or B cell comprising the antibody, wherein the antibody binds to the epitope sequence.

[0082] In some embodiments, the epitope sequence comprises one or more or each of the following: YLFDESGEFKL, YLFDESGEF, FGDDTVIEV, LLLDRLNQL, QLMCQPILL, TTDPSFLGRY, PTDNYITTY, PSFLGRY, AEAELAKNV, VATSRTLSY and KTIQPRVEK.

[0083] In some embodiments, the epitope sequence comprises one or more or each of the following: SAPPAQYEL, AVASKILGL, EYADVFHLY, DEFTPFDVV, VRIQPGQTF, SFRLFARTR, KFLPFQQF, VVQEGVLTA, RLDKVEAEV, FGADPIHSL, NYNYLYRLF, KYIKWPWYI, KWPWYIWLGF, LPFNDGVYF, QPTESIVRF, IPFAMQMAY, YLQPRTFLL and RLQSLQTYV.

[0084] In some embodiments, the epitope sequence is from an orflab protein.

[0085] In some embodiments, the epitope sequence is from an orfla protein

[0086] In some embodiments, the epitope sequence is from a surface glycoprotein(S) or a shifted reading frame thereof.

[0087] In some embodiments, the epitope sequence is from a nucleocapsid phosphoprotein (N).

[0088] In some embodiments, the epitope sequence is from an ORF3a protein.

[0089] In some embodiments, the epitope sequence is from a membrane glycoprotein (M).

[0090] In some embodiments, the epitope sequence is from an ORF7a protein.

[0091] In some embodiments, the epitope sequence is from an ORF8 protein.

[0092] In some embodiments, the epitope sequence is from an envelope protein (E).

[0093] In some embodiments, the epitope sequence is from an ORF6 protein.

[0094] In some embodiments, the epitope sequence is from an ORF7b protein.

[0095] In some embodiments, the epitope sequence is from an ORF10 protein.

[0096] In some embodiments, the epitope sequence is from an ORF9b protein.

[0097] Provided herein is a method of treating or preventing an infection by a virus or treating a respiratory disease or condition associated with an infection by a virus comprising administering to a subject with a B cell immunodeficiency a pharmaceutical composition comprising: a polypeptide having an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% sequence identity to a sequence of any one of the sequences depicted in column 2 of Table 11, column 2 of Table 12 or column 3 of Table 15; or a recombinant polynucleotide encoding a polypeptide having an amino acid sequence with at least at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of any one of the sequences depicted in column 2 of Table 11, column 2 of Table 12 or column 3 of Table 15.

[0098] In some embodiments, the pharmaceutical composition comprises a polypeptide with at least 70%, at least 75%, at least 80%, at least 85%, 90%, at least 95% or 100% sequence identity to a sequence selected from the group consisting of RS Clp1full, RS C2p1full, RS C3p1full, RS C4p1full, RS C5p1, RS C5p2, RS C5p2full, RS C6p1, RS C6p2, RS C6p2full, RS C7p1, RS C7p2, RS C7p2full, RS C7p4, RS C7p4full, RS C8p1, RS C8p2 and RS C8p2full; or a polynucleotide encoding a polypeptide with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence selected from the group consisting of RS C1p1full, RS C2p1full, RS C3p1full, RS C4p1full, RS C5p1, RS C5p2, RS C5p2full, RS C6p1, RS C6p2, RS C6p2full, RS C7p1, RS C7p2, RS C7p2full, RS C7p4, RS C7p4full, RS C8p1, RS C8p2 and RS C8p2full.

[0099] In some embodiments, the pharmaceutical composition comprises a polynucleotide with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: RS C1n1, RS C2n1, RS C3n1, RS C4n1, RS C5n1, RS Con1, RS C7n1, RS C8n1, RS C5n2, RS Con2, RS C7n2, RS C8n2, RS C5n2full, RS Con2full, RS C7n2full, RS C8n2full, RS C7n4, and RS C7n4full.

[0100] In some embodiments, the polynucleotide is an mRNA.

[0101] In some embodiments, the pharmaceutical composition further comprises one or more lipid components.

[0102] In some embodiments, the one or more lipid components comprise a lipid nanoparticle (LNP).

[0103] In some embodiments, the LNP encapsulates the recombinant polynucleotide construct.

[0104] In some embodiments, the polypeptide is synthetic.

[0105] In some embodiments, the polypeptide is recombinant.

[0106] In some embodiments, the polypeptide is from 8-1000 amino acids in length.

[0107] In some embodiments, the epitope sequence binds to or is predicted to bind to an HLA class I or class II molecule with a KD of 1000 nM or less.

[0108] In some embodiments, the epitope sequence binds to or is predicted to bind to an HLA class I or class II molecule with a KD of 500 nM or less.

[0109] In some embodiments, the epitope sequence comprises a sequence of a viral protein expressed by a virus-infected cell of the subject.

[0110] In some embodiments, the virus is a coronavirus.

[0111] In some embodiments, the virus is 2019 SARS-CoV 2.

[0112] In some embodiments, an HLA molecule expressed by the subject is unknown at the time of administration.

[0113] In some embodiments, the ability of the virus to avoid escape of recognition by an immune system of the subject is less compared to the ability of the virus to avoid escape of recognition by an immune system of a subject administered a pharmaceutical composition containing an epitope from a single protein or epitopes from fewer proteins than in the pharmaceutical composition administered according a method described herein.

[0114] In some embodiments, the subject expresses an HLA molecule encoded by an HLA allele of any one of Table 1A, Table 1B, Table 1C, Table 2Ai, Table 2Aii, Table 2B and Table 16 and the epitope sequence is an HLA allele-matched epitope sequence.

[0115] In some embodiments, the epitope sequence comprises one or more or each of the following: SAPPAQYEL, AVASKILGL, EYADVFHLY, DEFTPFDVV, VRIQPGQTF, SFRLFARTR, KFLPFQQF, VVQEGVLTA, RLDKVEAEV and FGADPIHSL.

[0116] In some embodiments, the method further comprises administering to the subject an additional therapy for a 2019 SARS-CoV 2 viral infection.

[0117] In some embodiments, the method further comprises administering to the subject (a) a polypeptide having an amino acid sequence of a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; (b) a recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; or a 2019 SARS-CoV 2 spike protein pharmaceutical composition comprising (a) or (b).

[0118] In some embodiments, the vaccine or therapeutic of (a) or (b) is administered to the subject once.

[0119] In some embodiments, the vaccine or therapeutic of (a) or (b) is administered to the subject more than once.

[0120] In some embodiments, the vaccine or therapeutic is administered at least two times, wherein the first administered dose is a priming dose, and the second and subsequent doses are booster dose(s).

[0121] In some embodiments, the priming and the booster doses are administered at an interval of at least 21 days.

[0122] In some embodiments, an interval between two booster doses is at least 30 days, at least 60 days, or at least 90 days.

[0123] In some embodiments, the vaccine or therapeutic is administered once each year.

[0124] In some embodiments, the vaccine or therapeutic is administered twice each year.

[0125] In some embodiments, the vaccine or therapeutic is administered at a high priming or loading dose for the first dose, and at a reduced boosting or maintenance dose for the subsequent doses.

[0126] In some embodiments, the subject receives a lower dose of or a lower frequency of a SARS-CoV spike vaccine than a subject receiving the SARS-CoV spike vaccine alone.

[0127] Provided herein is a method of treating or preventing an infection by a virus or treating a respiratory disease or condition associated with an infection by a virus comprising administering to a subject in need thereof a pharmaceutical composition comprising: (i) a recombinant polynucleotide encoding a polypeptide comprising at least two of the following: a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and (ii) a recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; wherein the ratio (e.g., mass ratio) of (i):(ii) is greater than 20:1 or less than 1:20.

[0128] In some embodiments, the ratio (e.g., mass ratio) of (i):(ii) is greater than 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1 or 100:1

[0129] In some embodiments, the ratio (e.g., mass ratio) of (i):(ii) is less than 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90 or 1:100.

[0130] Provided herein is a method of treating or preventing an infection by a virus or treating a respiratory disease or condition associated with an infection by a virus comprising administering to a subject in need thereof: (i) a first pharmaceutical composition comprising a first recombinant polynucleotide encoding a polypeptide comprising at least two of the following: a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and (ii) a second pharmaceutical composition comprising a second recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; wherein the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is from 1:50 to 50:1.

[0131] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is from about 1:25 to 25:1.

[0132] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is from about 1:10 to 10:1.

[0133] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is about 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 1:9.5, 1:8.5, 1:7.5, 1:6.5, 1:5.5, 1:4.5, 1:3.5, 1:2.5, 1:1.5, 2.5:1, 3.5:1, 4.5:1, 5.5:1, 6.5:1, 7.5:1, 8.5:1, 9.5:1, 2:9, 2:8, 2:7, 2:6, 2:5, 2:4, 2:3, 3:2, 4:2, 5:2, 6:2, 7:2, 8:2, 9:2, 3:8, 3:7, 3:5, 3:4, 4:3, 5:3, 7:3, 8:3, 4:9, 4:7, 4:5, 5:4, 7:4, 9:4, 5:9, 5:8, 5:7, 5:6, 6:5, 7:5, 8:5, 9:5, 6:7, 7:6, 7:8, 8:7, 8:9 or 9:8. In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is about 1:6. In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is about 1:3. In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is about 1:2.

[0134] In some embodiments, the recombinant polynucleotide in (i) is present in a pharmaceutical composition at a dose of from 0.1 microgram to 100 micrograms, or 1 microgram to 50 micrograms, or 1 microgram to 30 micrograms, or 1 microgram to 20 micrograms, or 3 micrograms to 20 micrograms, or 5 micrograms to 15 micrograms. In some embodiments, the recombinant polynucleotide in (i) is present in a pharmaceutical composition at a dose of from 0.05 microgram to 10 micrograms, or 0.1 microgram to 5 micrograms, or 0.3 microgram to 5 micrograms. In some embodiments, the recombinant polynucleotide in (i) is present in a pharmaceutical composition at a dose of from 0.1 microgram to 20 micrograms or from 0.5 microgram to 15 micrograms.

[0135] In some embodiments, the recombinant polynucleotide in (ii) is present in a pharmaceutical composition at a dose of from 0.1 microgram to 100 micrograms, or 1 microgram to 100 micrograms, or 1 microgram to 30 micrograms, or 1 microgram to 20 micrograms, or 3 micrograms to 30 micrograms.

[0136] In some embodiments, the recombinant polynucleotide in (i) is present in a pharmaceutical composition at a dose of about 5 micrograms and the recombinant polynucleotide in (ii) is present in a pharmaceutical composition at a dose of about 30 micrograms. In some embodiments, the recombinant polynucleotide in (i) is present in a pharmaceutical composition at a dose of about 10 micrograms and the recombinant polynucleotide in (ii) is present in a pharmaceutical composition at a dose of about 30 micrograms. In some embodiments, the recombinant polynucleotide in (i) is present in a pharmaceutical composition at a dose of about 15 micrograms and the recombinant polynucleotide in (ii) is present in a pharmaceutical composition at a dose of about 30 micrograms.

[0137] In some embodiments, the recombinant polynucleotide in (ii) encompasses at least two separate recombinant polynucleotides, each encoding a SARS-CoV-2 S protein of a different strain or variant thereof, or an immunogenic variant or fragment thereof (e.g., in some embodiments RBD). For example, in some embodiments, the recombinant polynucleotide in (ii) encompasses a recombinant polynucleotide encoding a SARS-CoV-2 S protein of an ancestral strain (e.g., Wuhan strain) or an immunogenic variant or fragment thereof (e.g., in some embodiments RBD) and a recombinant polynucleotide encoding a SARS-CoV-2 S protein of a SARS-CoV-2 variant strain that is prevalent or rapidly spreading at the time of administration. For example, in some embodiments, the recombinant polynucleotide in (ii) encompasses a recombinant polynucleotide encoding a SARS-CoV-2 S protein of an ancestral strain (e.g., Wuhan strain) or an immunogenic variant or fragment thereof (e.g., in some embodiments RBD) and a recombinant polynucleotide encoding a SARS-CoV-2 S protein of a variant strain having one or more mutations that are characteristics of a SARS-CoV-2 variant (e.g., in some embodiments an Omicron variant such as, e.g., a Omicron BA.1, BA.2, BA.4 or BA.5 variant), or an immunogenic variant or fragment thereof. In some embodiments, at least two recombinant polynucleotides, each encoding a SARS-CoV-2 S protein of a different strain or variant thereof, or an immunogenic variant or fragment thereof, can be present in a pharmaceutical composition at a ratio (e.g., mass ratio) of 3:1 to 1:3, or 2:1 to 1:2 or 1:1.

[0138] In some embodiments, a pharmaceutical composition described herein may further comprise (iii) a recombinant polynucleotide encoding a peptide or polypeptide antigen from a pathogen associated with a non-SARS-CoV-2 respiratory disease. In some embodiments, such a non-SARS-CoV-2 respiratory disease may be flu (influenza), and / or respiratory syncytial virus.

[0139] Provided herein is a method of treating or preventing an infection by a virus or treating a respiratory disease or condition associated with an infection by a virus comprising administering to a subject in need thereof a pharmaceutical composition comprising a nanoparticle, wherein the nanoparticle comprises: (i) a first recombinant polynucleotide encoding a polypeptide comprising at least two of the following: a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and (ii) a second recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof. In some embodiments, a first recombinant polynucleotide encodes a polypeptide comprising all of the following: a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N).

[0140] In some embodiments, the nanoparticle is present in the pharmaceutical composition at a dose of from 100 ng to 500 micrograms.

[0141] In some embodiments, the nanoparticle is present in the pharmaceutical composition at a dose of from 1 microgram to 100 micrograms.

[0142] In some embodiments, the nanoparticle is present in the pharmaceutical composition at a dose of from 1 microgram to 30 micrograms, 5 micrograms to 40 micrograms or 10 microgram to 50 micrograms.

[0143] In some embodiments, the nanoparticle is present in the pharmaceutical composition at a dose of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1,000 micrograms.

[0144] In some embodiments, the ratio (e.g., mass ratio) of the first recombinant polynucleotide to the second recombinant polynucleotide is from about 1:50 to 50:1.

[0145] In some embodiments, the ratio (e.g., mass ratio) of the first recombinant polynucleotide to the second recombinant polynucleotide is from about 1:25 to 25:1.

[0146] In some embodiments, the ratio (e.g., mass ratio) of the first recombinant polynucleotide to the second recombinant polynucleotide is from about 1:10 to 10:1.

[0147] In some embodiments, the ratio of the first recombinant polynucleotide to the second recombinant polynucleotide is about 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 1:9.5, 1:8.5, 1:7.5, 1:6.5, 1:5.5, 1:4.5, 1:3.5, 1:2.5, 1:1.5, 2.5:1, 3.5:1, 4.5:1, 5.5:1, 6.5:1, 7.5:1, 8.5:1, 9.5:1, 2:9, 2:8, 2:7, 2:6, 2:5, 2:4, 2:3, 3:2, 4:2, 5:2, 6:2, 7:2, 8:2, 9:2, 3:8, 3:7, 3:5, 3:4, 4:3, 5:3, 7:3, 8:3, 4:9, 4:7, 4:5, 5:4, 7:4, 9:4, 5:9, 5:8, 5:7, 5:6, 6:5, 7:5, 8:5, 9:5, 6:7, 7:6, 7:8, 8:7, 8:9 or 9:8. In some embodiments, the ratio (e.g., mass ratio) of the first recombinant polynucleotide to the second recombinant polynucleotide is about 1:6. In some embodiments, the ratio (e.g., mass ratio) of the first recombinant polynucleotide to the second recombinant polynucleotide is about 1:3. In some embodiments, the ratio (e.g., mass ratio) of the first recombinant polynucleotide to the second recombinant polynucleotide is about 1:2.

[0148] In some embodiments, the first recombinant polynucleotide is present in a pharmaceutical composition at a dose of from 0.1 microgram to 100 micrograms, or 1 microgram to 50 micrograms, or 1 microgram to 30 micrograms, or 1 microgram to 20 micrograms, or 3 micrograms to 20 micrograms, or 5 micrograms to 15 micrograms. In some embodiments, the first recombinant polynucleotide is present in a pharmaceutical composition at a dose of from 0.05 microgram to 10 micrograms, or 0.1 microgram to 5 micrograms, or 0.3 microgram to 5 micrograms. In some embodiments, the first recombinant polynucleotide is present in a pharmaceutical composition at a dose of from 0.1 microgram to 20 micrograms or from 0.5 microgram to 15 micrograms.

[0149] In some embodiments, the second recombinant polynucleotide is present in a pharmaceutical composition at a dose of from 0.1 microgram to 100 micrograms, or 1 microgram to 100 micrograms, or 1 microgram to 30 micrograms, or 1 microgram to 20 micrograms, or 3 micrograms to 30 micrograms.

[0150] In some embodiments, the second recombinant polynucleotide encompasses at least two separate recombinant polynucleotides, each encoding a SARS-CoV-2 S protein of a different strain or variant thereof, or an immunogenic variant or fragment thereof (e.g., in some embodiments RBD). For example, in some embodiments, the second recombinant polynucleotide encompasses a recombinant polynucleotide encoding a SARS-CoV-2 S protein of an ancestral strain (e.g., Wuhan strain) or an immunogenic variant or fragment thereof (e.g., in some embodiments RBD) and a recombinant polynucleotide encoding a SARS-CoV-2 S protein of a SARS-CoV-2 variant strain that is prevalent or rapidly spreading at the time of administration. For example, in some embodiments, the second recombinant polynucleotide encompasses a recombinant polynucleotide encoding a SARS-CoV-2 S protein of an ancestral strain (e.g., Wuhan strain) or an immunogenic variant or fragment thereof (e.g., in some embodiments RBD) and a recombinant polynucleotide encoding a SARS-CoV-2 S protein of a variant strain having one or more mutations that are characteristics of a SARS-CoV-2 variant (e.g., in some embodiments an Omicron variant such as, e.g., an Omicron BA.1, BA.2, BA.4 or BA.5 variant), or an immunogenic variant or fragment thereof. In some embodiments, the two recombinant polynucleotides, each encoding a SARS-CoV-2 S protein of a different strain or variant thereof, or an immunogenic variant or fragment thereof, can be present in a pharmaceutical composition at a ratio (e.g., mass ratio) of 3:1 to 1:3, or 2:1 to 1:2 or 1:1.

[0151] In some embodiments, a pharmaceutical composition described herein may comprise a third recombinant polynucleotide encoding a peptide or polypeptide antigen from a pathogen associated with a non-SARS-CoV-2 respiratory disease. In some embodiments, such a non-SARS-CoV-2 respiratory disease may be, but not limited to flu (influenza), and / or respiratory syncytial virus.

[0152] Provided herein is a method of treating or preventing an infection by a virus or treating a respiratory disease or condition associated with an infection by a virus comprising administering to a subject in need thereof: (i) a first pharmaceutical composition comprising a first nanoparticle, wherein the first nanoparticle comprises a recombinant polynucleotide encoding a polypeptide comprising at least two of the following: a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and (ii) a second pharmaceutical composition comprising a second nanoparticle, wherein the second nanoparticle comprises a recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof. In some embodiments, a first pharmaceutical composition comprising a first nanoparticle, wherein the first nanoparticle comprises a recombinant polynucleotide encoding a polypeptide comprising all of the following: a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N).

[0153] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is from about 1:50 to 50:1.

[0154] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is from about 1:25 to 25:1.

[0155] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is from about 1:10 to 10:1.

[0156] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is about 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 1:9.5, 1:8.5, 1:7.5, 1:6.5, 1:5.5, 1:4.5, 1:3.5, 1:2.5, 1:1.5, 2.5:1, 3.5:1, 4.5:1, 5.5:1, 6.5:1, 7.5:1, 8.5:1, 9.5:1, 2:9, 2:8, 2:7, 2:6, 2:5, 2:4, 2:3, 3:2, 4:2, 5:2, 6:2, 7:2, 8:2, 9:2, 3:8, 3:7, 3:5, 3:4, 4:3, 5:3, 7:3, 8:3, 4:9, 4:7, 4:5, 5:4, 7:4, 9:4, 5:9, 5:8, 5:7, 5:6, 6:5, 7:5, 8:5, 9:5, 6:7, 7:6, 7:8, 8:7, 8:9 or 9:8. In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is about 1:6. In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is about 1:3. In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is about 1:2.

[0157] In some embodiments, the recombinant polynucleotide in (i) is present in a pharmaceutical composition at a dose of from 0.1 microgram to 100 micrograms, or 1 microgram to 50 micrograms, or 1 microgram to 30 micrograms, or 1 microgram to 20 micrograms, or 3 micrograms to 20 micrograms, or 5 micrograms to 15 micrograms. In some embodiments, the recombinant polynucleotide in (i) is present in a pharmaceutical composition at a dose of from 0.05 microgram to 10 micrograms, or 0.1 microgram to 5 micrograms, or 0.3 microgram to 5 micrograms. In some embodiments, the recombinant polynucleotide in (i) is present in a pharmaceutical composition at a dose of from 0.1 microgram to 20 micrograms or from 0.5 microgram to 15 micrograms.

[0158] In some embodiments, the recombinant polynucleotide in (ii) is present in a pharmaceutical composition at a dose of from 0.1 microgram to 100 micrograms, or 1 microgram to 100 micrograms, or 1 microgram to 30 micrograms, or 1 microgram to 20 micrograms, or 3 micrograms to 30 micrograms.

[0159] In some embodiments, the recombinant polynucleotide in (ii) encompasses at least two separate recombinant polynucleotides, each encoding a SARS-CoV-2 S protein of a different strain or variant thereof, or an immunogenic variant or fragment thereof (e.g., in some embodiments RBD). For example, in some embodiments, the recombinant polynucleotide in (ii) encompasses a recombinant polynucleotide encoding a SARS-CoV-2 S protein of an ancestral strain (e.g., Wuhan strain) or an immunogenic variant or fragment thereof (e.g., in some embodiments RBD) and a recombinant polynucleotide encoding a SARS-CoV-2 S protein of a SARS-CoV-2 variant strain that is prevalent or rapidly spreading at the time of administration. For example, in some embodiments, the recombinant polynucleotide in (ii) encompasses a recombinant polynucleotide encoding a SARS-CoV-2 S protein of an ancestral strain (e.g., Wuhan strain) or an immunogenic variant or fragment thereof (e.g., in some embodiments RBD) and a recombinant polynucleotide encoding a SARS-CoV-2 S protein of a variant strain having one or more mutations that are characteristics of a SARS-CoV-2 variant (e.g., in some embodiments an Omicron variant such as, e.g., a Omicron BA.1, BA.2, BA.4 or BA.5 variant), or an immunogenic variant or fragment thereof. In some embodiments, at least two recombinant polynucleotides, each encoding a SARS-CoV-2 S protein of a different strain or variant thereof, or an immunogenic variant or fragment thereof, can be present in a pharmaceutical composition at a ratio (e.g., mass ratio) of 3:1 to 1:3, or 2:1 to 1:2 or 1:1.

[0160] In some embodiments, a third pharmaceutical composition (iii) may be administered to a subject in need thereof, which comprises a third nanoparticle, wherein the third nanoparticle comprises a recombinant polynucleotide encoding a peptide or polypeptide antigen from a pathogen associated with a non-SARS-CoV-2 respiratory disease. In some embodiments, such a non-SARS-CoV-2 respiratory disease may be flu (influenza), and / or respiratory syncytial virus.

[0161] In some embodiments, the first nanoparticle is present in the first pharmaceutical composition at a dose of from about 100 ng to 500 micrograms.

[0162] In some embodiments, the first nanoparticle is present in the first pharmaceutical composition at a dose of from about 1 microgram to 100 micrograms.

[0163] In some embodiments, the first nanoparticle is present in the first pharmaceutical composition at a dose of from about 1 microgram to 30 micrograms, 5 micrograms to 40 micrograms or 10 microgram to 50 micrograms.

[0164] In some embodiments, the first nanoparticle is present in the first pharmaceutical composition at a dose of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1,000 micrograms.

[0165] In some embodiments, the second nanoparticle is present in the second pharmaceutical composition at a dose of from about 100 ng to 500 micrograms.

[0166] In some embodiments, the second nanoparticle is present in the second pharmaceutical composition at a dose of from about 1 microgram to 100 micrograms.

[0167] In some embodiments, the second nanoparticle is present in the second pharmaceutical composition at a dose of from about 1 microgram to 30 micrograms, 5 micrograms to 40 micrograms or 10 microgram to 50 micrograms.

[0168] In some embodiments, the second nanoparticle is present in the second pharmaceutical composition at a dose of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1,000 micrograms.

[0169] Provided herein is a method of treating or preventing an infection by a virus or treating a respiratory disease or condition associated with an infection by a virus comprising administering to a subject in need thereof: (i) a pharmaceutical composition comprising (a) a polypeptide comprising at least two of the following: a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); or (b) a polynucleotide encoding a polypeptide comprising at least two of the following: a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and (ii) a pharmaceutical composition comprising (a) a polypeptide having an amino acid sequence of a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; or (b) a recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; or a 2019 SARS-CoV 2 spike protein pharmaceutical composition comprising (ii)(a) or (ii)(b); wherein the subject receives a dose of (ii)(a) or (ii)(b) that is lower than a dose of (ii)(a) or (ii)(b) administered to a subject alone.

[0170] Provided herein is a method of treating or preventing an infection by a virus or treating a respiratory disease or condition associated with an infection by a virus comprising administering to a subject in need thereof: (i) a pharmaceutical composition comprising (a) a polypeptide comprising at least two of the following: a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); or (b) a polynucleotide encoding a polypeptide comprising at least two of the following: a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and (ii) a pharmaceutical composition comprising (a) a polypeptide having an amino acid sequence of a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; or (b) a recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; or a 2019 SARS-CoV 2 spike protein pharmaceutical composition comprising (ii)(a) or (ii)(b).

[0171] Provided herein is a method of treating or preventing an infection by a virus or treating a respiratory disease or condition associated with an infection by a virus comprising administering to a subject in need thereof: (i) a pharmaceutical composition comprising (a) a polypeptide comprising at least two of the following: a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); or (b) a polynucleotide encoding a polypeptide comprising at least two of the following: a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and (ii) a pharmaceutical composition comprising (a) a polypeptide having an amino acid sequence of a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; (b) a recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; or a 2019 SARS-CoV 2 spike protein pharmaceutical composition comprising (ii)(a) or (ii)(b); wherein the subject receives a number of doses of (ii)(a) or (ii)(b) that is lower than a number of doses of (ii)(a) or (ii)(b) administered to a subject alone.

[0172] In some embodiments, the subject receives a dose of (ii)(a) or (ii)(b) that is at least 1.1, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 times lower than a dose of (ii)(a) or (ii)(b) administered to a subject alone.

[0173] In some embodiments, the subject receives 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 fewer doses of (ii)(a) or (ii)(b) than the number of doses of (ii)(a) or (ii)(b) administered to a subject alone.

[0174] In some embodiments, the pharmaceutical composition of (i) is co-formulated with the pharmaceutical composition of (ii).

[0175] In some embodiments, the pharmaceutical composition of (i) is formulated separately from the pharmaceutical composition of (ii).

[0176] In some embodiments, the pharmaceutical composition of (i) is administered separately from the pharmaceutical composition of (ii).

[0177] Provided herein is a method of treating or preventing an infection by a virus or treating a respiratory disease or condition associated with an infection by a virus comprising administering to a subject in need thereof: (i) a pharmaceutical composition comprising (a) a polypeptide comprising at least two of the following: a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); or (b) a polynucleotide encoding a polypeptide comprising at least two of the following: a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and (ii) a pharmaceutical composition comprising (a) a polypeptide having an amino acid sequence of a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; (b) a recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; or a 2019 SARS-CoV 2 spike protein pharmaceutical composition comprising (ii)(a) or (ii)(b); wherein the subject receives a dose of (i)(a) or (i)(b) that is lower than a dose of (i)(a) or (i)(b) administered to a subject alone.

[0178] Provided herein is a method of treating or preventing an infection by a virus or treating a respiratory disease or condition associated with an infection by a virus comprising administering to a subject in need thereof: (i) a pharmaceutical composition comprising (a) a polypeptide comprising at least two of the following: a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); or (b) a polynucleotide encoding a polypeptide comprising at least two of the following: a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and (ii) a pharmaceutical composition comprising (a) a polypeptide having an amino acid sequence of a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; (b) a recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; or a 2019 SARS-CoV 2 spike protein pharmaceutical composition comprising (ii)(a) or (ii)(b); wherein the subject receives a number of doses of (i)(a) or (i)(b) that is lower than a number of doses of (i)(a) or (i)(b) administered to a subject alone.

[0179] In some embodiments, the subject receives a dose of (i)(a) or (i)(b) that is at least 1.1, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 times lower than a dose of (i)(a) or (i)(b) administered to a subject alone.

[0180] In some embodiments, the subject receives 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 fewer doses of (i)(a) or (i)(b) than the number of doses of (i)(a) or (i)(b) administered to a subject alone.

[0181] In some embodiments, the pharmaceutical composition of (i) is co-formulated with the pharmaceutical composition of (ii).

[0182] In some embodiments, the pharmaceutical composition of (i) is formulated separately from the pharmaceutical composition of (ii).

[0183] In some embodiments, the pharmaceutical composition of (i) is administered separately from the pharmaceutical composition of (ii).

[0184] In some embodiments, the pharmaceutical composition is a coformulation.

[0185] In some embodiments, the first pharmaceutical composition is administered with or on the same day as the second pharmaceutical composition

[0186] In some embodiments, the first pharmaceutical composition is administered simultaneously with the second pharmaceutical composition.

[0187] In some embodiments, the first pharmaceutical composition is administered at a first location of the subject and the second pharmaceutical composition is administered at a second location of the subject that is different than the first location.

[0188] In some embodiments, the first location is at an appendage of the subject and second location is at an opposing appendage of the subject,

[0189] In some embodiments, the first appendage is an arm and the second appendage is an arm.

[0190] In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are administered to the same location of the subject.

[0191] In some embodiments, the pharmaceutical composition is administered at a first time point and a second time point, wherein the second time point is at least about, at most about or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 days after the first time point; at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 weeks after the first time point; or at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 months after the first time point.

[0192] In some embodiments, the pharmaceutical composition is administered at a third time point, wherein the third time point is at least about, at most about or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 days after the second time point; at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 weeks after the second time point; or at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 months after the second time point.

[0193] In some embodiments, the third time point is at least about, at most about or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 days after the first time point; at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 weeks after the first time point; or at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 months after the first time point.

[0194] In some embodiments, the first pharmaceutical composition is administered at a first time point and a second time point, wherein the second time point is at least about, at most about or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 days after the first time point; at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 weeks after the first time point; or at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 months after the first time point.

[0195] In some embodiments, the first pharmaceutical composition is administered at a third time point, wherein the third time point is at least about, at most about or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 days after the second time point; at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 weeks after the second time point; or at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 months after the second time point.

[0196] In some embodiments, the third time point is at least about, at most about or about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 days after the first time point; at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 weeks after the first time point; or at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 months after the first time point.

[0197] In some embodiments, the second pharmaceutical composition is administered at the first time point.

[0198] In some embodiments, the second pharmaceutical composition is administered at the second time point.

[0199] In some embodiments, the second pharmaceutical composition is administered at the third time point.

[0200] In some embodiments, the second pharmaceutical composition is administered at least about, at most about or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 days after the first time point; at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 weeks after the first time point; or at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 months after the first time point.

[0201] In some embodiments, the second pharmaceutical composition is administered at least about, at most about or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 days after the second time point; at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 weeks after the second time point; or at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 months after the second time point.

[0202] Provided herein is a method of treating or preventing an infection by a virus or treating a respiratory disease or condition associated with an infection by a virus comprising administering to a subject in need thereof: (i) a pharmaceutical composition comprising (a) a polypeptide comprising at least two of the following: a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); or (b) a polynucleotide encoding a polypeptide comprising at least two of the following: a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); wherein the pharmaceutical composition is administered at a first time point, a second time point and a third time point, wherein the second time point is at least about 2 days after the first time point and the third time point is at least about 2 days after the second time point.

[0203] In some embodiments, the second time point is at least about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days after the first time point, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 weeks after the first time point, or at least about 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 months after the first time point.

[0204] In some embodiments, the second time point is at most about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days after the first time point, at most about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 weeks after the first time point, or at most about 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 months after the first time point.

[0205] In some embodiments, the second time point is about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days after the first time point, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 weeks after the first time point, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 months after the first time point.

[0206] In some embodiments, the third time point is at least about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days after the second time point, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 weeks after the second time point, or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 months after the second time point.

[0207] In some embodiments, the third time point is at most about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days after the second time point, at most about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 weeks after the second time point, or at most about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 months after the second time point.

[0208] In some embodiments, the third time point is about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35 days after the second time point, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 weeks after the second time point, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 months after the second time point.

[0209] In some embodiments, the third time point is at least about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 days after the first time point, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 weeks after the first time point, or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 months after the first time point.

[0210] In some embodiments, the third time point is at most about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 days after the first time point, at most about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 weeks after the first time point, or at most about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 months after the first time point.

[0211] In some embodiments, the third time point about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 days after the first time point, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 weeks after the first time point, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 months after the first time point.

[0212] In some embodiments, the method further comprises administering to the subject: (ii)(a) a polypeptide having an amino acid sequence of a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; (b) a recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; or a 2019 SARS-CoV 2 spike protein pharmaceutical composition comprising (ii)(a) or (ii)(b).

[0213] In some embodiments, the subject has an immunodeficiency.

[0214] In some embodiments, the subject has a B cell immunodeficiency.

[0215] In some embodiments, the pharmaceutical composition is administered prophylactically.

[0216] Provided herein is a pharmaceutical composition comprising: (i) a recombinant polynucleotide encoding a polypeptide comprising at least two of the following: a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and (ii) a recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; wherein the ratio (e.g., mass ratio) of (i):(ii) is greater than 20:1 or less than 1:20.

[0217] In some embodiments, the ratio (e.g., mass ratio) of (i):(ii) is greater than 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1 or 100:1

[0218] In some embodiments, the ratio (e.g., mass ratio) of (i):(ii) is less than 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90 or 1:100.

[0219] Provided herein is a composition comprising: (i) a first pharmaceutical composition comprising a first recombinant polynucleotide encoding a polypeptide comprising at least two of the following: a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and (ii) a second pharmaceutical composition comprising a second recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; wherein the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is from 1:50 to 50:1.

[0220] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is from about 1:25 to 25:1.

[0221] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is from about 1:10 to 10:1.

[0222] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is about 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 1:9.5, 1:8.5, 1:7.5, 1:6.5, 1:5.5, 1:4.5, 1:3.5, 1:2.5, 1:1.5, 2.5:1, 3.5:1, 4.5:1, 5.5:1, 6.5:1, 7.5:1, 8.5:1, 9.5:1, 2:9, 2:8, 2:7, 2:6, 2:5, 2:4, 2:3, 3:2, 4:2, 5:2, 6:2, 7:2, 8:2, 9:2, 3:8, 3:7, 3:5, 3:4, 4:3, 5:3, 7:3, 8:3, 4:9, 4:7, 4:5, 5:4, 7:4, 9:4, 5:9, 5:8, 5:7, 5:6, 6:5, 7:5, 8:5, 9:5, 6:7, 7:6, 7:8, 8:7, 8:9 or 9:8. In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is about 1:6. In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is about 1:3. In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is about 1:2.

[0223] In some embodiments, the recombinant polynucleotide in (i) is present at a dose of from 0.1 microgram to 100 micrograms, or 1 microgram to 50 micrograms, or 1 microgram to 30 micrograms, or 1 microgram to 20 micrograms, or 3 micrograms to 20 micrograms, or 5 micrograms to 15 micrograms. In some embodiments, the recombinant polynucleotide in (i) is present at a dose of from 0.05 microgram to 10 micrograms, or 0.1 microgram to 5 micrograms, or 0.3 microgram to 5 micrograms. In some embodiments, the recombinant polynucleotide in (i) is present at a dose of from 0.1 microgram to 20 micrograms or from 0.5 microgram to 15 micrograms.

[0224] In some embodiments, the recombinant polynucleotide in (ii) is present at a dose of from 0.1 microgram to 100 micrograms, or 1 microgram to 100 micrograms, or 1 microgram to 30 micrograms, or 1 microgram to 20 micrograms, or 3 micrograms to 30 micrograms.

[0225] In some embodiments, the recombinant polynucleotide in (ii) encompasses at least two recombinant polynucleotide, each encoding a SARS-CoV-2 S protein of a different strain or variant thereof. For example, in some embodiments, the recombinant polynucleotide in (ii) encompasses a recombinant polynucleotide encoding a SARS-CoV-2 protein of a Wuhan strain and a recombinant polynucleotide encoding a SARS-CoV-2 protein having one or more mutations that are characteristics of a SARS-CoV-2 variant (e.g., in some embodiments an Omicron variant such as, e.g., a Omicron BA.4 or BA.5).

[0226] In some embodiments, the recombinant polynucleotide in (i) is present at a dose of about 5 micrograms and the recombinant polynucleotide in (ii) is present at a dose of about 30 micrograms. In some embodiments, the recombinant polynucleotide in (i) is present at a dose of about 10 micrograms and the recombinant polynucleotide in (ii) is present at a dose of about 30 micrograms. In some embodiments, the recombinant polynucleotide in (i) is present at a dose of about 15 micrograms and the recombinant polynucleotide in (ii) is present at a dose of about 30 micrograms.

[0227] Provided herein is a pharmaceutical composition comprising a nanoparticle, wherein the nanoparticle comprises: (i) a first recombinant polynucleotide encoding a polypeptide comprising at least two of the following: a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and (ii) a second recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof.

[0228] In some embodiments, the nanoparticle is present in the pharmaceutical composition at a dose of from 100 ng to 500 micrograms.

[0229] In some embodiments, the nanoparticle is present in the pharmaceutical composition at a dose of from 1 microgram to 100 micrograms.

[0230] In some embodiments, the nanoparticle is present in the pharmaceutical composition at a dose of from 1 microgram to 30 micrograms, 5 micrograms to 40 micrograms or 10 microgram to 50 micrograms.

[0231] In some embodiments, the nanoparticle is present in the pharmaceutical composition at a dose of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1,000 micrograms.

[0232] In some embodiments, the ratio (e.g., mass ratio) of the first recombinant polynucleotide to the second recombinant polynucleotide is from about 1:50 to 50:1.

[0233] In some embodiments, the ratio (e.g., mass ratio) of the first recombinant polynucleotide to the second recombinant polynucleotide is from about 1:25 to 25:1.

[0234] In some embodiments, the ratio (e.g., mass ratio) of the first recombinant polynucleotide to the second recombinant polynucleotide is from about 1:10 to 10:1.

[0235] In some embodiments, the ratio (e.g., mass ratio) of the first recombinant polynucleotide to the second recombinant polynucleotide is about 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 1:9.5, 1:8.5, 1:7.5, 1:6.5, 1:5.5, 1:4.5, 1:3.5, 1:2.5, 1:1.5, 2.5:1, 3.5:1, 4.5:1, 5.5:1, 6.5:1, 7.5:1, 8.5:1, 9.5:1, 2:9, 2:8, 2:7, 2:6, 2:5, 2:4, 2:3, 3:2, 4:2, 5:2, 6:2, 7:2, 8:2, 9:2, 3:8, 3:7, 3:5, 3:4, 4:3, 5:3, 7:3, 8:3, 4:9, 4:7, 4:5, 5:4, 7:4, 9:4, 5:9, 5:8, 5:7, 5:6, 6:5, 7:5, 8:5, 9:5, 6:7, 7:6, 7:8, 8:7, 8:9 or 9:8. In some embodiments, the ratio (e.g., mass ratio) of the first recombinant polynucleotide to the second recombinant polynucleotide is about 1:6. In some embodiments, the ratio (e.g., mass ratio) of the first recombinant polynucleotide to the second recombinant polynucleotide is about 1:3. In some embodiments, the ratio (e.g., mass ratio) of the first recombinant polynucleotide to the second recombinant polynucleotide is about 1:2.

[0236] In some embodiments, the first recombinant polynucleotide is present in a pharmaceutical composition at a dose of from 0.1 microgram to 100 micrograms, or 1 microgram to 50 micrograms, or 1 microgram to 30 micrograms, or 1 microgram to 20 micrograms, or 3 micrograms to 20 micrograms, or 5 micrograms to 15 micrograms. In some embodiments, the first recombinant polynucleotide is present in a pharmaceutical composition at a dose of from 0.05 microgram to 10 micrograms, or 0.1 microgram to 5 micrograms, or 0.3 microgram to 5 micrograms. In some embodiments, the first recombinant polynucleotide is present in a pharmaceutical composition at a dose of from 0.1 microgram to 20 micrograms or from 0.5 microgram to 15 micrograms.

[0237] In some embodiments, the second recombinant polynucleotide is present in a pharmaceutical composition at a dose of from 0.1 microgram to 100 micrograms, or 1 microgram to 100 micrograms, or 1 microgram to 30 micrograms, or 1 microgram to 20 micrograms, or 3 micrograms to 30 micrograms.

[0238] In some embodiments, the second recombinant polynucleotide encompasses at least two recombinant polynucleotide, each encoding a SARS-CoV-2 S protein of a different strain or variant thereof. For example, in some embodiments, the second recombinant polynucleotide encompasses a recombinant polynucleotide encoding a SARS-CoV-2 S protein of a Wuhan strain and a recombinant polynucleotide encoding a SARS-CoV-2 S protein having one or more mutations that are characteristics of a SARS-CoV-2 variant (e.g., in some embodiments an Omicron variant such as, e.g., an Omicron BA.1, BA.2, BA.4 or BA.5 variant).

[0239] Provided herein is a composition comprising: (i) a first pharmaceutical composition comprising a first nanoparticle, wherein the first nanoparticle comprises a recombinant polynucleotide encoding a polypeptide comprising at least two of the following: a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and (ii) a second pharmaceutical composition comprising a second nanoparticle, wherein the second nanoparticle comprises a recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof.

[0240] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is from about 1:50 to 50:1.

[0241] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is from about 1:25 to 25:1.

[0242] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is from about 1:10 to 10:1.

[0243] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is about 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 1:9.5, 1:8.5, 1:7.5, 1:6.5, 1:5.5, 1:4.5, 1:3.5, 1:2.5, 1:1.5, 2.5:1, 3.5:1, 4.5:1, 5.5:1, 6.5:1, 7.5:1, 8.5:1, 9.5:1, 2:9, 2:8, 2:7, 2:6, 2:5, 2:4, 2:3, 3:2, 4:2, 5:2, 6:2, 7:2, 8:2, 9:2, 3:8, 3:7, 3:5, 3:4, 4:3, 5:3, 7:3, 8:3, 4:9, 4:7, 4:5, 5:4, 7:4, 9:4, 5:9, 5:8, 5:7, 5:6, 6:5, 7:5, 8:5, 9:5, 6:7, 7:6, 7:8, 8:7, 8:9 or 9:8. In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is about 1:6. In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is about 1:3. In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is about 1:2.

[0244] In some embodiments, the recombinant polynucleotide in (i) is present at a dose of from 0.1 microgram to 100 micrograms, or 1 microgram to 50 micrograms, or 1 microgram to 30 micrograms, or 1 microgram to 20 micrograms, or 3 micrograms to 20 micrograms, or 5 micrograms to 15 micrograms. In some embodiments, the recombinant polynucleotide in (i) is present at a dose of from 0.05 microgram to 10 micrograms, or 0.1 microgram to 5 micrograms, or 0.3 microgram to 5 micrograms. In some embodiments, the recombinant polynucleotide in (i) is present at a dose of from 0.1 microgram to 20 micrograms or from 0.5 microgram to 15 micrograms.

[0245] In some embodiments, the recombinant polynucleotide in (ii) is present at a dose of from 0.1 microgram to 100 micrograms, or 1 microgram to 100 micrograms, or 1 microgram to 30 micrograms, or 1 microgram to 20 micrograms, or 3 micrograms to 30 micrograms.

[0246] In some embodiments, the recombinant polynucleotide in (ii) encompasses at least two recombinant polynucleotide, each encoding a SARS-CoV-2 S protein of a different strain or variant thereof. For example, in some embodiments, the recombinant polynucleotide in (ii) encompasses a recombinant polynucleotide encoding a SARS-CoV-2 protein of a Wuhan strain and a recombinant polynucleotide encoding a SARS-CoV-2 protein having one or more mutations that are characteristics of a SARS-CoV-2 variant (e.g., in some embodiments an Omicron variant such as, e.g., a Omicron BA.4 or BA.5).

[0247] In some embodiments, the first nanoparticle is present in the first pharmaceutical composition at a dose of from about 100 ng to 500 micrograms.

[0248] In some embodiments, the first nanoparticle is present in the first pharmaceutical composition at a dose of from about 1 microgram to 100 micrograms.

[0249] In some embodiments, the first nanoparticle is present in the first pharmaceutical composition at a dose of from about 1 microgram to 30 micrograms, 5 micrograms to 40 micrograms or 10 microgram to 50 micrograms.

[0250] In some embodiments, the first nanoparticle is present in the first pharmaceutical composition at a dose of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1,000 micrograms.

[0251] In some embodiments, the second nanoparticle is present in the second pharmaceutical composition at a dose of from about 100 ng to 500 micrograms.

[0252] In some embodiments, the second nanoparticle is present in the second pharmaceutical composition at a dose of from about 1 microgram to 100 micrograms.

[0253] In some embodiments, the second nanoparticle is present in the second pharmaceutical composition at a dose of from about 1 microgram to 30 micrograms, 5 micrograms to 40 micrograms or 10 microgram to 50 micrograms.

[0254] In some embodiments, the second nanoparticle is present in the second pharmaceutical composition at a dose of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1,000 micrograms.

[0255] In some embodiments, the recombinant polynucleotide in (i) is present in the first pharmaceutical composition at a dose of from about 50 ng to 250 micrograms.

[0256] In some embodiments, the recombinant polynucleotide in (i) is present in the first pharmaceutical composition at a dose of from about 0.5 to 50 micrograms.

[0257] In some embodiments, the recombinant polynucleotide in (i) is present in the first pharmaceutical composition at a dose of from about 0.5 microgram to 15 micrograms, 2.5 micrograms to 20 micrograms or 5 microgram to 25 micrograms.

[0258] In some embodiments, the recombinant polynucleotide in (i) is present in the first pharmaceutical composition at a dose of about 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450 or 500 micrograms.

[0259] In some embodiments, the recombinant polynucleotide in (ii) is present in the second pharmaceutical composition at a dose of from about 50 ng to 250 micrograms.

[0260] In some embodiments, the recombinant polynucleotide in (ii) is present in the second pharmaceutical composition at a dose of from about 0.5 to 50 micrograms.

[0261] In some embodiments, the recombinant polynucleotide in (ii) is present in the second pharmaceutical composition at a dose of from about 0.5 microgram to 15 micrograms, 2.5 micrograms to 20 micrograms or 5 microgram to 25 micrograms.

[0262] In some embodiments, the recombinant polynucleotide in (ii) is present in the second pharmaceutical composition at a dose of about 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450 or 500 micrograms.

[0263] In some embodiments, the nanoparticle is a lipid nanoparticle.

[0264] Provided herein is a method of treating or preventing an infection by a virus or treating a respiratory disease or condition associated with an infection by a virus comprising administering to a subject in need thereof a pharmaceutical composition comprising: (i) a polypeptide comprising at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, (b) a sequence comprising an epitope sequence from membrane glycoprotein (M) and (c) a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); (ii) a polynucleotide encoding a polypeptide, wherein the polypeptide comprises at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, (b) a sequence comprising an epitope sequence from membrane glycoprotein (M) and (c) a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); (iii) a T cell receptor (TCR) or a T cell comprising the TCR, wherein the TCR binds to an epitope sequence of the polypeptide in complex with a corresponding HLA class I or class II molecule; (iv) an antigen presenting cell comprising (i) or (ii); or (v) an antibody or B cell comprising the antibody, wherein the antibody binds to an epitope sequence of the polypeptide.

[0265] In some embodiments, the subject has an immunodeficiency.

[0266] In some embodiments, the subject has a B cell immunodeficiency.

[0267] In some embodiments, the subject has a reduced ability to produce an antibody response to an antigen compared to a subject without an immunodeficiency.

[0268] In some embodiments, the subject has a reduced ability to produce an antibody response to a vaccination compared to a subject without an immunodeficiency.

[0269] In some embodiments, the subject has a reduced ability to produce an anti-spike protein antibody response and / or an anti-RBD antibody response compared to a subject without an immunodeficiency.

[0270] In some embodiments, the subject can produce a T cell response or does not have a reduced ability to produce a T cell response compared to a subject without an immunodeficiency.

[0271] In some embodiments, the pharmaceutical composition is protective against a variant of 2019 SARS CoV-2.

[0272] In some embodiments, the variant of 2019 SARS CoV-2 is alpha, beta, gamma, delta, epsilon, zeta, eta, theta, iota, kappa or lambda.

[0273] In some embodiments, the subject produces a T cell response to an epitope of the polypeptide.

[0274] In some embodiments, the subject produces a T cell response to the epitope sequence from ORF1ab, the epitope sequence from membrane glycoprotein (M) and / or the epitope sequence from nucleocapsid phosphoprotein (N).

[0275] In some embodiments, the subject is an organ transplant recipient.

[0276] In some embodiments, the organ transplant recipient is a sold organ transplant recipient, a stem cell transplant recipient or a bone marrow transplant recipient.

[0277] In some embodiments, the subject received an organ transplant less than 1 year, less than 6 months or less than 3 months after the pharmaceutical composition is administered.

[0278] In some embodiments, the subject is expected to receive an organ transplant less than 1 year, less than 6 months or less than 3 months prior to the pharmaceutical composition being administered.

[0279] In some embodiments, the subject has a cancer.

[0280] In some embodiments, the cancer is a B cell cancer.

[0281] In some embodiments, the B cell cancer is a B cell lymphoma or a B cell leukemia.

[0282] In some embodiments, the subject has an autoimmune disease or condition.

[0283] In some embodiments, the autoimmune disease or condition is Addison disease, Anti-NMDA receptor encephalitis, antisynthetase syndrome, Aplastic anemia, autoimmune anemias, Autoimmune hemolytic anemia, Autoimmune pancreatitis, Behcet's Disease, bullous skin disorders, Celiac disease-sprue, chronic fatigue syndrome, Chronic inflammatory demyelinating polyneuropathy, chronic lymphocytic leukemia, Crohn's disease, Dermatomyositis, Devic's disease, Erythroblastopenia, Evans syndrome, Focal segmental glomerulosclerosis, Granulomatosis with polyangiitis, Graves disease, Graves' ophthalmopathy, Guillain-Barre syndrome, Hashimoto thyroiditis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, IgA-mediated autoimmune diseases, IgG4-related disease, Inflammatory bowel disease, Juvenile idiopathic arthritis, Multiple sclerosis, Myasthenia gravis, myeloma, non-Hodgkin's lymphoma, Opsoclonus myoclonus syndrome (OMS), Pemphigoid, Pemphigus, pemphigus vulgaris, Pernicious anemia, polymyositis, Psoriasis, pure red cell aplasia, Reactive arthritis, Rheumatoid arthritis, Sarcoidosis, scleroderma, Sjögren syndrome, Systemic lupus erythematosus, Thrombocytopenia purpura, Thrombotic thrombocytopeniaurpura, Type I diabetes, Ulcerative colitis, Vasculitis and Vitiligo.

[0284] In some embodiments, the subject has congenital agammaglobulinemia or congenital IgA deficiency.

[0285] In some embodiments, the subject has HIV or AIDS. In some embodiments, the subject has an age-related decline in immunity, immunosenescence, multifactoral immunodeficiency, or is an elderly or older adult with an age-related immunodeficiency.

[0286] In some embodiments, the subject is receiving an immunosuppressive agent or has received an immunosuppressive agent less than 1 year, less than 6 months or less than 3 months prior to the administering of the pharmaceutical composition.

[0287] In some embodiments, the immunosuppressive agent is abatacept, abrilumab, acalabrutinib, adalimumab, adrenocorticotropic hormone, agatolimod sodium, aldesleukin, alefacept, alemtuzumab, alisertib, alvespimycin hydrochloride, alvocidib, ambrisentan, aminocamptothecin, amiselimod, anakinra, andecaliximab, andrographolides, anifrolumab, antithymocyte Ig, apatinib, apelisib, asparaginase, atacicept, atezolizumab, avelumab, azacitidine, azathioprine, bafetinib, baminercept, baricitinib, basiliximab, becatecarin, begelomab, belatacept, belimumab, bemcentinib, bendamustine, bendamustine, betalutin with lilotomab, bevacizumab, BIIB033, BIIB059, BIIB061, bimekizumab, binimetinib, bleomycin, blinatumomab, bortezomib, brentuximab vedotin, bryostatin 1, bucillamine, buparlisib, busulfan, canakinumab, capecitabine, carboplatin, carfilzomib, carmustine, cediranib maleate, cemiplimab, ceralifimod, cerdulatinib, certolizumab, cetuximab, chidamide, chlorambucil, cilengitide, cirmtuzumab, cisplatin, cladribine, clazakizumab, clemastine, clioquinol, corticosteroids, cyclophosphamide, cyclosporine, cytarabine, cytotoxic chemotherapy, daclizumab, dalfampridine, daprolizumab pegol, daratumumab, dasatinib, defactinib, defibrotide, denosumab, dexamethasone, diacerein, dimethyl fumarate, dinaciclib, diroximel fumarate, doxorubicin, doxorubicin, durvalumab, duvelisib, duvortuxizumab, eculizumab, efalizumab, eftilagimod alpha, a neuropeptide combination of metenkefalin and tridecactide, elezanumab, elotuzumab, encorafenib, enfuvirtida, entinostat, entospletinib, enzastaurin, epacadostat, epirubicin, epratuzumab, eritoran tetrasodium, etanercept, etoposide, etrolizumab, everolimus, evobrutinib, filgotinib, fingolimod, firategrast, fludarabine, fluorouracil, fontolizumab, forodesine hydrochloride, fostamatinib, galunisertib, ganetespib, ganitumab, gemcitabine, gemtuzumab ozogamicin, gerilimzumab, glasdegib, glassia, glatiramer acetate, glembatumumab vedotin, glesatinib, golimumab, guadecitabine, hydrocortisone, hydroxychloroquine sulfate, hydroxyurea, ibritumomab tiuxetan, ibrutinib, ibudilast, idarubicin, idebenone, idelalisib, ifosfamide, iguratimod, imatinib, imexon, infliximab, inotuzumab ozogamicin, interferon alfa-2, interferon beta-la, interferon beta-1b, interferon gamma-1, ipilimumab, irofulven, isatuximab, ispinesib, itacitinib, ixazomib, lapatinib, laquinimod, laromustine, ld-aminopterin, leflunomide, lenalidomide, lenvatinib, letrozole, levamisole, levocabastine, lipoic acid, lirilumab, lonafarnib, lumiliximab, maraviroc, masitinib, mavrilimumab, melphalan, mercaptopurine, methotrexate, methoxsalen, methylprednisone, milatuzumab, mitoxantrone, mizoribine, mocetinostat, monalizumab, mosunetuzumab, motesanib diphosphate, moxetumomab pasudotox, muromonab-CD3, mycophenolate mofetil, mycophenolic acid, namilumab, natalizumab, navitoclax, neihulizumab, nerispirdine, neurovax, niraparib, nivolumab, obatoclax mesylate, obinutuzumab, oblimersen sodium, ocrelizumab, ofatumumab, olokizumab, opicinumab, oprelvekin, osimertinib, otelixizumab, oxaliplatin, oxcarbazepine, ozanimod, paclitaxel, pacritinib, palifermin, panobinostat, pazopanib, peficitinib, pegfilgrastim, peginterferon beta-la, pegsunercept (peg stnf-ri), pembrolizumab, pemetrexed, penclomedine, pentostatin, perifosine, pevonedistat, pexidartinib, picoplatin, pidilizumab, pivanex, pixantrone, pleneva, plovamer acetate, polatuzumab vedotin, pomalidomide, ponatinib, ponesimod, prednisone / prednisolone, pyroxamide, ravulizimab-cwvz, recombinant il-12, relatlimab, rhigf-1, rhigm22, rigosertib, rilonacept, ritonavir, rituximab, ruxolitinib, sarilumab, secukinumab, selumetinib, simvastatin, sintilimab, siplizumab, siponimod, sirolimus (rapamycin), sirukumab, sitravatinib, sonidegib, sorafenib, sotrastaurin acetate, sunitinib, sunphenon epigallocatechin-gallate, tabalumab, tacrolimus, talabostat mesylate, talacotuzumab, tanespimycin, tegafur / gimeracil / oteracil, temozolomide, temsirolimus, tenalisib, terameprocol, teriflunomide, thalidomide, thiarabine, thiotepa, tipifarnib, tirabrutinib, tislelizumab, tivozanib, tocilizumab, tofacitinib, tregalizumab, tremelimumab, treosulfan, ublituximab, umbralisib, upadacitinib, urelumab, ustekinumab, varlilumab, vatelizumab, vedolizumab, veliparib, veltuzumab, venetoclax, vinblastine, vincristine, vinorelbine ditartrate, visilizumab, vismodegib, vistusertib, voriconazole, vorinostat, vosaroxin, ziv-aflibercept or any combination thereof.

[0288] In some embodiments, the immunosuppressive agent is A2aR antagonist, Akt inhibitor, anti CD20, Anti-amyloidotic (AA) Agent, anti-CD37 protein therapeutic, anti-CTLA4 mAb, Anti-CXCR4, anti-huCD40 mAb, anti-LAG3 mAb, anti-PD-1 mAb, anti-PD-L1 agent, anti-PD-L1 agent, anti-PD-L1 mAb, anti-TGFb mAb, anti-TIGIT mAb, anti-TIM-3 mAb, Aurora kinase inhibitor, Bcl-2 Inhibitor, bifunctional fusion protein targeting TGFb and PD-L1, bispecific anti-PD-1 and anti-LAG3 mAb, CD1d ligand, CD40 agonist, Complement C5a inhibitor, CSF1R inhibitor, EZH2 inhibitor, FGFR3 inhibitor, FGFR4 inhibitor, FGFrR3 inhibitor, glucocorticoid-induced tumor necrosis factor receptor-related gene agonist, glutaminase inhibitor, Human monoclonal antibody against IL-12, ICOS agonist, IDO1 inhibitor, IL2 mutein, IL2 receptor agonist, MEK inhibitor, multitargeted receptor tyrosine kinase inhibitor, neutrophil elastase inhibitor, Notch Inhibitor, p38 MAPK inhibitor, PD-1 inhibitor, recombinant human Flt3L, ROCK inhibitor, selective sphingosine-1-phosphate receptor modulator, Src kinase inhibitor, TLR4 agonist, TLR9 agonist, or any combination thereof.

[0289] In some embodiments, the subject is greater than 55, 56, 57, 58, 59, 60, 65, 70, 75 or 80 years of age.

[0290] In some embodiments, the polypeptide comprises (a) a sequence comprising an epitope sequence from ORF1ab, (b) a sequence comprising an epitope sequence from membrane glycoprotein (M) and (c) a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N).

[0291] In some embodiments, the sequence comprising an epitope sequence from ORF1ab is C-terminal to the sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N).

[0292] In some embodiments, the sequence comprising an epitope sequence from ORF1ab is N-terminal to the sequence comprising an epitope sequence from membrane glycoprotein (M).

[0293] In some embodiments, the sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N) is N-terminal to the sequence comprising an epitope sequence from membrane glycoprotein (M).

[0294] In some embodiments, the polypeptide comprises (a) 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more epitope sequences from ORF1ab, (b) a sequence comprising an epitope sequence from membrane glycoprotein (M) and (c) a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N).

[0295] In some embodiments, the epitope sequence from ORF1ab is an epitope sequence from a non-structural protein (NSP).

[0296] In some embodiments, the non-structural protein (NSP) is selected from the group consisting of NSP1, NSP2, NSP3, NSP4 and combinations thereof.

[0297] In some embodiments, the polypeptide comprises a sequence comprising an epitope sequence from NSP1, a sequence comprising an epitope sequence from NSP2, a sequence comprising an epitope sequence from NSP3 and a sequence comprising an epitope sequence from NSP4.

[0298] In some embodiments, the epitope sequence from ORF1ab is selected from the group consisting of YLFDESGEFKL, YLFDESGEF, FGDDTVIEV, QLMCQPILL, TTDPSFLGRY, PTDNYITTY, PSFLGRY, AEAELAKNV, KTIQPRVEK and any combination thereof.

[0299] In some embodiments, the epitope sequence from nucleocapsid glycoprotein (N) is LLLDRLNQL.

[0300] In some embodiments, the epitope sequence from membrane phosphoprotein (M) is VATSRTLSY.

[0301] In some embodiments, the polypeptide comprises an epitope sequence from nucleocapsid glycoprotein (N) that is LLLDRLNQL and an epitope sequence from membrane phosphoprotein (M) that is VATSRTLSY.

[0302] In some embodiments, the polypeptide comprises (a) each of the following epitope sequences from ORF1ab: YLFDESGEFKL, YLFDESGEF, FGDDTVIEV, QLMCQPILL, TTDPSFLGRY, PTDNYITTY, PSFLGRY, AEAELAKNV, KTIQPRVEK; (b) an epitope sequence from nucleocapsid glycoprotein (N) that is LLLDRLNQL; and (c) an epitope sequence from membrane phosphoprotein (M) that is VATSRTLSY.

[0303] In some embodiments, the sequence comprising an epitope sequence from ORF1ab is selected from the group fragments thereof: consisting of the following sequences orMVTNNTFTLKVPHVGEIPVAYRKVLLKTIQPRVEKYLFDESGEFKLSEVGPEHSLAEYYIFFASFYY; MVTNNTFTLKVPHVGEIPVAYRKVLLKTIQPRVEKYLFDESGEFKLSEVGPEHSLAEY; APKEIIFLEGETLFGDDTVIEVAIILASFSAST; APKEIIFLEGETLFGDDTVIEV; HTTDPSFLGRYMSALFADDLNQLTGYHTDFSSEIIGYQLMCQPILLAEAELAKNVSLILGTVSWNL; TTDPSFLGRYMSALFADDLNQLTGYHTDFSSEIIGYQLMCQPILLAEAELAKNVSLILGTVSWNL; LLSAGIFGAITDVFYKENSYKVPTDNYITTY; and combinations thereof.

[0304] In some embodiments, the sequence comprising an epitope sequence from membrane glycoprotein (M) is selected from the group consisting of the following sequences or fragments thereof:ADSNGTITVEELKKLLEQWNLVIGFLFLTWICLLQFAYANRNRFLYIIKLIFLWLLWPVTLACFVLAAVYRINWITGGIAIAMACLVGLMWLSYFIASFRLFARTRSMWSFNPETNILLNVPLHGTILTRPLLESELVIGAVILRGHLRIAGHHLGRCDIKDLPKEITVATSRTLSYYKLGASQRVAGDSGFAAYSRYRIGNYKLNTDHSSSSDNIALLVQ; FAYANRNRFLYIIKLIFLWLLWPVTLACFVLAAVYRINWITGGIAIAMACLVGLMWLSYFIASFRLF; LGRCDIKDLPKEITVATSRTLSYYKLGASQRVA; KLLEQWNLVIGF; NRNRFLYII KLIFLWLLWPVTLACFVLAAVY; SELVIGAVILRGHLRIAGHHLGR; VATSRTLSYYKLGASQRV; GLMWLSYF; and combinationsthereof.

[0305] In some embodiments, the sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N) is selected from the group consisting of the following sequences or fragments thereof:KDLSPRWYFYYLGTGPEAGLPYGANKDGIIWVATEGALNTPKDHIGTRNPANNAAIVLQLPQGTTLPKGFYAEGSRGGSQASSRSSSRSRNSSRNSTPGSSRGTSPARMAGNGGDAALALLLLDRLNQLESKMSGKGQQQQGQTVTKKSAAEASKKPRQKRTATKAYNVTQAFGRRGPEQTQGNFGDQELIRQGTDYKHWPQIAQFAPSASAFFGMSRIGMEVTPSGTWLTYTGAIKLDDKDPNFKDQVILLNKHIDAYKTFPPTEPKKDKKKKADETQALPQRQKKQQTVTLLPAADLDDFSKQLQQSMSSADSTQA; RMAGNGGDAALALLLLDRLNQLESKMSGKGQQQ; YKHWPQIAQFAPSASAFFGMSRIGMEVTPSGTWLTYTGAIKLDDKDPNFKDQVILLNKHIDAYKTFP; SPARMAGNGGDAALALLLLDRLNQLESKMSGKGQQQQGQTVTKKSAAEASKKPRQKRTATKAYNVTQAFGRRGPEQTQGNFGDQELIRQGTDYKHWPQIAQFAPSASAFFGMSRIGMEVTPSGTWLTYTGAIKLDDKDPNFKDQVILLNKHIDAYKTFPPTEPKKDK and combinations thereof.

[0306] In some embodiments, the polypeptide comprises one or more linker sequences.

[0307] In some embodiments, the one or more linker sequences are selected from the group consisting of GGSGGGGSGG, GGSLGGGGSG.

[0308] In some embodiments, the one or more linker sequences comprise cleavage sequences.

[0309] In some embodiments, the one or more cleavage sequences are selected from the group consisting of FRAC, KRCF, KKRY, ARMA, RRSG, MRAC, KMCG, ARCA, KKQG, YRSY, SFMN, FKAA, KRNG, YNSF, KKNG, RRRG, KRYS, and ARYA.

[0310] In some embodiments, the polypeptide comprises a transmembrane domain sequence.

[0311] In some embodiments, the transmembrane domain sequence is C-terminal to the sequence comprising an epitope sequence from ORF1ab, the sequence comprising an epitope sequence from membrane glycoprotein (M) and the sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N).

[0312] In some embodiments, the transmembrane domain sequence is EQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKL HYT.

[0313] In some embodiments, the polypeptide comprises a secretory signal sequence (SEC sequence).

[0314] In some embodiments, the SEC sequence is N-terminal to the sequence comprising an epitope sequence from ORF1ab, the sequence comprising an epitope sequence from membrane glycoprotein (M) and the sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N).

[0315] In some embodiments, the SEC sequence is MFVFLVLLPLVSSQCVNLT.

[0316] In some embodiments, the composition comprises the polynucleotide encoding the polypeptide.

[0317] In some embodiments, the polynucleotide is an mRNA.

[0318] In some embodiments, the polynucleotide comprises a codon optimized sequence for expression in a human.

[0319] In some embodiments, the polynucleotide comprises a dEarI-hAg sequence.

[0320] In some embodiments, the dEarI-hAg sequence is ATTCTTCTGGTCCCCACAGACTCAGAGAGAACCC, optionally wherein each T is a U.

[0321] In some embodiments, the polynucleotide comprises a Kozak sequence.

[0322] In some embodiments, the Kozak sequence is GCCACC.

[0323] In some embodiments, the polynucleotide comprises an F element sequence.

[0324] In some embodiments, the F element sequence is a 3 UTR of amino-terminal enhancer of split (AES).

[0325] In some embodiments, the F element sequence is CTGGTACTGCATGCACGCAATGCTAGCTGCCCCTTTCCCGTCCTGGGTACCCCGAGTCTCCC CCGACCTCGGGTCCCAGGTATGCTCCCACCTCCACCTGCCCCACTCACCACCTCTGCTAGTTC CAGACACCTCC, optionally wherein each T is a U.

[0326] In some embodiments, the polynucleotide comprises an I element sequence.

[0327] In some embodiments, the I element sequence is a 3′ UTR of mitochondrially encoded 12S rRNA (mtRNR1).

[0328] In some sequence is embodiments, the I element CAAGCACGCAGCAATGCAGCTCAAAACGCTTAGCCTAGCCACACCCCCACGGGAAACAGCA GTGATTAACCTTTAGCAATAAACGAAAGTTTAACTAAGCTATACTAACCCCAGGGTTGGTCA

[0329] ATTTCGTGCCAGCCACACC, optionally wherein each T is a U.

[0330] In some embodiments, the polynucleotide comprises a poly A sequence.

[0331] In some embodiments, the poly A sequence is AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAGCATATGACTAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA, optionally wherein each T is a U.

[0332] In some embodiments, each of the epitope sequences from the ORF1ab, the membrane glycoprotein, and the nucleocapsid phosphoprotein are from 2019 SARS-CoV-2.

[0333] In some embodiments, one or more or each epitope elicits a T cell response.

[0334] In some embodiments, one or more or each epitope has been observed by mass spectrometry as being presented by an HLA molecule.

[0335] In some embodiments, the composition comprises (i) a polypeptide with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% sequence identity to a sequence selected from the group consisting of RS Clp1full, RS C2p1full, RS C3p1full, RS C4p1full, RS C5p1, RS C5p2, RS C5p2full, RS C6p1, RS C6p2, RS C6p2full, RS C7p1, RS C7p2, RS C7p2full, RS C7p4, RS C7p4full, RS C8p1, RS C8p2 and RS C8p2full; (ii) a polynucleotide encoding a polypeptide with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence selected from the group consisting of RS C1p1full, RS C2p1full, RS C3p1full, RS C4p1full, RS C5p1, RS C5p2, RS C5p2full, RS C6p1, RS C6p2, RS C6p2full, RS C7p1, RS C7p2, RS C7p2full, RS C7p4, RS C7p4full, RS C8p1, RS C8p2 and RS C8p2full; or (iii) a polynucleotide with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: RS C1n1, RS C2n1, RS C3n1, RS C4n1, RS C5n1, RS Con1, RS C7n1, RS C8n1, RS C5n2, RS C6n2, RS C7n2, RS C8n2, RS C5n2full, RS Con2full, RS C7n2full, RS C8n2full, RS C7n4, RS C7n4full.

[0336] In some embodiments, the composition comprises (i) a polypeptide with at least 70%, 80%, 90% or 100% sequence identity to a sequence selected from the group consisting of RS C7p1, RS C7p2, RS C7p2full, RS C7p4, and RS C7p4full; or (iii) a polynucleotide with at least at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: RS C7n1, RS C7n2, RS C7n2full, RS C7n4, RS and C7n4full.

[0337] In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient, carrier, or diluent.

[0338] Provided herein is a method of treating or preventing an infection by a virus or treating a respiratory disease or condition associated with an infection by a virus comprising administering to a subject in need thereof a pharmaceutical composition comprising: (i) a polypeptide comprising an epitope sequence of Table 1A, Table 1B, Table 1C, Table 2Ai, Table 2Aii, Table 2B and / or Table 16; (ii) a polynucleotide encoding the polypeptide comprising an epitope sequence of Table 1A, Table 1B, Table 1C, Table 2Ai, Table 2Aii, Table 2B and / or Table 16; (iii) a T cell receptor (TCR) or a T cell comprising the TCR, wherein the TCR binds to the epitope sequence in complex with a corresponding HLA class I or class II molecule; (iv) an antigen presenting cell comprising (i) or (ii); or (v) an antibody or B cell comprising the antibody, wherein the antibody binds to the epitope sequence.

[0339] In some embodiments, the subject has an immunodeficiency.

[0340] In some embodiments, the subject has a B cell immunodeficiency.

[0341] In some embodiments, the epitope sequence comprises one or more or each of the following: YLFDESGEFKL, YLFDESGEF, FGDDTVIEV, LLLDRLNQL, QLMCQPILL, TTDPSFLGRY, PTDNYITTY, PSFLGRY, AEAELAKNV, VATSRTLSY and KTIQPRVEK.

[0342] In some embodiments, the epitope sequence comprises one or more or each of the following: SAPPAQYEL, AVASKILGL, EYADVFHLY, DEFTPFDVV, VRIQPGQTF, SFRLFARTR, KFLPFQQF, VVQEGVLTA, RLDKVEAEV, FGADPIHSL, NYNYLYRLF, KYIKWPWYI, KWPWYIWLGF, LPFNDGVYF, QPTESIVRF, IPFAMQMAY, YLQPRTFLL and RLQSLQTYV.

[0343] In some embodiments, the epitope sequence is from an orflab protein.

[0344] In some embodiments, the epitope sequence is from an orfla protein

[0345] In some embodiments, the epitope sequence is from a surface glycoprotein(S) or a shifted reading frame thereof.

[0346] In some embodiments, the epitope sequence is from a nucleocapsid phosphoprotein (N).

[0347] In some embodiments, the epitope sequence is from an ORF3a protein.

[0348] In some embodiments, the epitope sequence is from a membrane glycoprotein (M).

[0349] In some embodiments, the epitope sequence is from an ORF7a protein.

[0350] In some embodiments, the epitope sequence is from an ORF8 protein.

[0351] In some embodiments, the epitope sequence is from an envelope protein (E).

[0352] In some embodiments, the epitope sequence is from an ORF6 protein.

[0353] In some embodiments, the epitope sequence is from an ORF7b protein.

[0354] In some embodiments, the epitope sequence is from an ORF10 protein.

[0355] In some embodiments, the epitope sequence is from an ORF9b protein.

[0356] Provided herein is a method of treating or preventing an infection by a virus or treating a respiratory disease or condition associated with an infection by a virus comprising administering to a subject in need thereof a pharmaceutical composition comprising: a polypeptide having an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of any one of the sequences depicted in column 2 of Table 11, column 2 of Table 12 or column 3 of Table 15; or a recombinant polynucleotide encoding a polypeptide having an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of any one of the sequences depicted in column 2 of Table 11, column 2 of Table 12 or column 3 of Table 15.

[0357] In some embodiments, the subject has an immunodeficiency.

[0358] In some embodiments, the subject has a B cell immunodeficiency.

[0359] In some embodiments, the pharmaceutical composition comprises a polypeptide with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence selected from the group consisting of RS C1p1full, RS C2p1full, RS C3p1full, RS C4p1full, RS C5p1, RS C5p2, RS C5p2full, RS C6p1, RS C6p2, RS C6p2full, RS C7p1, RS C7p2, RS C7p2full, RS C7p4, RS C7p4full, RS C8p1, RS C8p2 and RS C8p2full; or a polynucleotide encoding a polypeptide with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence selected from the group consisting of RS Clp1full, RS C2p1full, RS C3p1full, RS C4p1full, RS C5p1, RS C5p2, RS C5p2full, RS C6p1, RS C6p2, RS C6p2full, RS C7p1, RS C7p2, RS C7p2full, RS C7p4, RS C7p4full, RS C8p1, RS C8p2 and RS C8p2full.

[0360] In some embodiments, the pharmaceutical composition comprises a polynucleotide with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: RS C1n1, RS C2n1, RS C3n1, RS C4n1, RS C5n1, RS Con1, RS C7n1, RS C8n1, RS C5n2, RS Con2, RS C7n2, RS C8n2, RS C5n2full, RS Con2full, RS C7n2full, RS C8n2full, RS C7n4, and RS C7n4full.

[0361] In some embodiments, the polynucleotide is an mRNA.

[0362] In some embodiments, the pharmaceutical composition further comprises one or more lipids.

[0363] In some embodiments, the one or more lipids comprise a lipid nanoparticle (LNP).

[0364] In some embodiments, the LNP encapsulates the recombinant polynucleotide construct.

[0365] In some embodiments, the polypeptide is synthetic.

[0366] In some embodiments, the polypeptide is recombinant.

[0367] In some embodiments, the polypeptide is from 8-1000 amino acids in length.

[0368] In some embodiments, the epitope sequence binds to or is predicted to bind to an HLA class I or class II molecule with a KD of 1000 nM or less.

[0369] In some embodiments, the epitope sequence binds to or is predicted to bind to an HLA class I or class II molecule with a KD of 500 nM or less.

[0370] In some embodiments, the epitope sequence comprises a sequence of a viral protein expressed by a virus-infected cell of the subject.

[0371] In some embodiments, the virus is a coronavirus.

[0372] In some embodiments, the virus is 2019 SARS-CoV 2.

[0373] In some embodiments, an HLA molecule expressed by the subject is unknown at the time of administration.

[0374] In some embodiments, the ability of the virus to avoid escape of recognition by an immune system of the subject is less compared to the ability of the virus to avoid escape of recognition by an immune system of a subject administered a pharmaceutical composition containing an epitope from a single protein or epitopes from fewer proteins than in the pharmaceutical composition administered according to a method described herein.

[0375] In some embodiments, the subject expresses an HLA molecule encoded by an HLA allele of any one of Table 1A, Table 1B, Table 1C, Table 2Ai, Table 2Aii, Table 2B and Table 16 and the epitope sequence is an HLA allele-matched epitope sequence.

[0376] In some embodiments, the epitope sequence comprises one or more or each of the following: SAPPAQYEL, AVASKILGL, EYADVFHLY, DEFTPFDVV, VRIQPGQTF, SFRLFARTR, KFLPFQQF, VVQEGVLTA, RLDKVEAEV and FGADPIHSL.

[0377] In some embodiments, the method further comprises administering to the subject an additional therapy for a 2019 SARS-CoV 2 viral infection.

[0378] In some embodiments, the method further comprises administering to the subject (a) a polypeptide having an amino acid sequence of a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; (b) a recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; or a 2019 SARS-CoV 2 spike protein pharmaceutical composition comprising (a) or (b).

[0379] In some embodiments, the vaccine or therapeutic of (a) or (b) is administered to the subject once.

[0380] In some embodiments, the vaccine or therapeutic of (a) or (b) is administered to the subject more than once.

[0381] In some embodiments, the vaccine or therapeutic of (a) or (b) is administered at least two times, wherein the first administered dose is a priming dose, and the second and subsequent doses are booster dose(s). In some embodiments, the vaccine or therapeutic of (a) or (b) is administered at least three times, wherein the first administered dose is a priming dose, and the second, third, and subsequent doses are booster dose(s).

[0382] In some embodiments, the priming and the booster doses are administered at an interval of at least 21 days.

[0383] In some embodiments, an interval between two booster doses is at least 30 days, at least 60 days or at least 90 days.

[0384] In some embodiments, the vaccine or therapeutic is administered once each year.

[0385] In some embodiments, the vaccine or therapeutic is administered twice each year.

[0386] In some embodiments, the vaccine or therapeutic is administered at a high priming or loading dose for the first dose, and at a reduced boosting or maintenance dose for the subsequent doses.

[0387] In some embodiments, the subject receives a lower dose of or a lower frequency of a SARS-CoV spike vaccine than a subject receiving the SARS-CoV spike vaccine alone.

[0388] Provided herein is a method of treating or preventing an infection by a virus or treating a respiratory disease or condition associated with an infection by a virus comprising administering to a subject in need thereof a pharmaceutical composition comprising: (i) a recombinant polynucleotide encoding a polypeptide comprising at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and (ii) a recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof.

[0389] In some embodiments, provided herein is a method of treating or preventing an infection by a virus or treating a respiratory disease or condition associated with an infection by a virus comprising administering to a subject in need thereof: (i) a first pharmaceutical composition comprising a first recombinant polynucleotide encoding a polypeptide comprising at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and (ii) a second pharmaceutical composition comprising a second recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof.

[0390] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is from 20:1 to 1:20.

[0391] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is from 1:10 to 10:1.

[0392] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is from about 1:5 to 5:1.

[0393] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is from about 1:3 to 3:1.

[0394] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is about 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 1:9.5, 1:8.5, 1:7.5, 1:6.5, 1:5.5, 1:4.5, 1:3.5, 1:2.5, 1:1.5, 2.5:1, 3.5:1, 4.5:1, 5.5:1, 6.5:1, 7.5:1, 8.5:1, 9.5:1, 2:9, 2:8, 2:7, 2:6, 2:5, 2:4, 2:3, 3:2, 4:2, 5:2, 6:2, 7:2, 8:2, 9:2, 3:8, 3:7, 3:5, 3:4, 4:3, 5:3, 7:3, 8:3, 4:9, 4:7, 4:5, 5:4, 7:4, 9:4, 5:9, 5:8, 5:7, 5:6, 6:5, 7:5, 8:5, 9:5, 6:7, 7:6, 7:8, 8:7, 8:9 or 9:8.

[0395] In some embodiments, a method of treating or preventing an infection comprises administering the first pharmaceutical composition (i) and the second pharmaceutical composition (ii), to a subject who has previously been administered one or more doses of a SARS-CoV-2 vaccine (e.g., a SARS-CoV-2 vaccine that comprises (a) a polypeptide that includes a SARS-CoV-2 spike protein, or a fragment or variant thereof, or (b) a recombinant polynucleotide comprising a sequence that encodes a SARS-CoV-2 spike protein or a fragment or variant thereof). In some embodiments, a method of treating or preventing an infection comprises administering the first pharmaceutical composition (i) and the second pharmaceutical composition (ii) to a subject who has previously been administered two or more (e.g., three) doses of a SARS-CoV-2 vaccine.

[0396] In some embodiments, provided herein is a method of treating or preventing an infection by a virus or treating a respiratory disease or condition associated with an infection by a virus comprising administering to a subject in need thereof a pharmaceutical composition comprising: (i) a first recombinant polynucleotide encoding a polypeptide comprising at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and (ii) a second recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof.

[0397] In some embodiments, the pharmaceutical composition comprises a nanoparticle, wherein the nanoparticle comprises the first recombinant polynucleotide and the second recombinant polynucleotide.

[0398] In some embodiments, the nanoparticle is present in the pharmaceutical composition at a dose of from 100 ng to 500 micrograms.

[0399] In some embodiments, the nanoparticle is present in the pharmaceutical composition at a dose of from 1 microgram to 100 micrograms.

[0400] In some embodiments, the nanoparticle is present in the pharmaceutical composition at a dose of from 1 microgram to 30 micrograms, 5 micrograms to 40 micrograms or 10 microgram to 50 micrograms.

[0401] In some embodiments, the nanoparticle is present in the pharmaceutical composition at a dose of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1,000 micrograms.

[0402] In some embodiments, the ratio (e.g., mass ratio) of the first recombinant polynucleotide to the second recombinant polynucleotide is from about 1:50 to 50:1.

[0403] In some embodiments, the ratio (e.g., mass ratio) of the first recombinant polynucleotide to the second recombinant polynucleotide is from about 1:25 to 25:1.

[0404] In some embodiments, the ratio (e.g., mass ratio) of the first recombinant polynucleotide to the second recombinant polynucleotide is from about 1:10 to 10:1.

[0405] In some embodiments, the ratio (e.g., mass ratio) of the first recombinant polynucleotide to the second recombinant polynucleotide is about 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 1:9.5, 1:8.5, 1:7.5, 1:6.5, 1:5.5, 1:4.5, 1:3.5, 1:2.5, 1:1.5, 2.5:1, 3.5:1, 4.5:1, 5.5:1, 6.5:1, 7.5:1, 8.5:1, 9.5:1, 2:9, 2:8, 2:7, 2:6, 2:5, 2:4, 2:3, 3:2, 4:2, 5:2, 6:2, 7:2, 8:2, 9:2, 3:8, 3:7, 3:5, 3:4, 4:3, 5:3, 7:3, 8:3, 4:9, 4:7, 4:5, 5:4, 7:4, 9:4, 5:9, 5:8, 5:7, 5:6, 6:5, 7:5, 8:5, 9:5, 6:7, 7:6, 7:8, 8:7, 8:9 or 9:8.

[0406] Provided herein is a method of treating or preventing an infection by a virus or treating a respiratory disease or condition associated with an infection by a virus comprising administering to a subject in need thereof: (i) a first pharmaceutical composition comprising a recombinant polynucleotide encoding a polypeptide comprising at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and (ii) a second pharmaceutical composition comprising a recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof.

[0407] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is from about 1:50 to 50:1.

[0408] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is from about 1:25 to 25:1.

[0409] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is from about 1:10 to 10:1.

[0410] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is about 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 1:9.5, 1:8.5, 1:7.5, 1:6.5, 1:5.5, 1:4.5, 1:3.5, 1:2.5, 1:1.5, 2.5:1, 3.5:1, 4.5:1, 5.5:1, 6.5:1, 7.5:1, 8.5:1, 9.5:1, 2:9, 2:8, 2:7, 2:6, 2:5, 2:4, 2:3, 3:2, 4:2, 5:2, 6:2, 7:2, 8:2, 9:2, 3:8, 3:7, 3:5, 3:4, 4:3, 5:3, 7:3, 8:3, 4:9, 4:7, 4:5, 5:4, 7:4, 9:4, 5:9, 5:8, 5:7, 5:6, 6:5, 7:5, 8:5, 9:5, 6:7, 7:6, 7:8, 8:7, 8:9 or 9:8.

[0411] In some embodiments, the first pharmaceutical composition comprises a first nanoparticle, wherein the first nanoparticle comprises the recombinant polynucleotide encoding a polypeptide comprising at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and wherein the second pharmaceutical composition comprises a second nanoparticle, wherein the second nanoparticle comprises the recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof.

[0412] In some embodiments, the first nanoparticle is present in the first pharmaceutical composition at a dose of from about 100 ng to 500 micrograms.

[0413] In some embodiments, the first nanoparticle is present in the first pharmaceutical composition at a dose of from about 1 microgram to 100 micrograms.

[0414] In some embodiments, the first nanoparticle is present in the first pharmaceutical composition at a dose of from about 1 microgram to 30 micrograms, 5 micrograms to 40 micrograms or 10 microgram to 50 micrograms.

[0415] In some embodiments, the first nanoparticle is present in the first pharmaceutical composition at a dose of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1,000 micrograms.

[0416] In some embodiments, the second nanoparticle is present in the second pharmaceutical composition at a dose of from about 100 ng to 500 micrograms.

[0417] In some embodiments, the second nanoparticle is present in the second pharmaceutical composition at a dose of from about 1 microgram to 100 micrograms.

[0418] In some embodiments, the second nanoparticle is present in the second pharmaceutical composition at a dose of from about 1 microgram to 30 micrograms, 5 micrograms to 40 micrograms or 10 microgram to 50 micrograms.

[0419] In some embodiments, the second nanoparticle is present in the second pharmaceutical composition at a dose of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1,000 micrograms.

[0420] Provided herein is a method of treating or preventing an infection by a virus or treating a respiratory disease or condition associated with an infection by a virus comprising administering to a subject in need thereof: (i) a pharmaceutical composition comprising (a) a polypeptide comprising at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); or (b) a polynucleotide encoding a polypeptide comprising at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and (ii)(a) a pharmaceutical composition comprising a polypeptide having an amino acid sequence of a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; (b) a recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; or a 2019 SARS-CoV 2 spike protein pharmaceutical composition comprising (ii)(a) or (ii)(b);

[0421] wherein the subject receives a dose of (ii)(a) or (ii)(b) that is lower than a dose of (ii)(a) or (ii)(b) administered to a subject alone.

[0422] Provided herein is a method of treating or preventing an infection by a virus or treating a respiratory disease or condition associated with an infection by a virus comprising administering to a subject in need thereof: (i) a pharmaceutical composition comprising (a) a polypeptide comprising at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); or (b) a polynucleotide encoding a polypeptide comprising at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and (ii)(a) a pharmaceutical composition comprising a polypeptide having an amino acid sequence of a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; (b) a recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; or a 2019 SARS-CoV 2 spike protein pharmaceutical composition comprising (ii)(a) or (ii)(b);

[0423] wherein the subject receives a number of doses of (ii)(a) or (ii)(b) that is lower than a number of doses of (ii)(a) or (ii)(b) administered to a subject alone.

[0424] In some embodiments, the subject receives a dose of (ii)(a) or (ii)(b) that is at least 1.1, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 times lower than a dose of (ii)(a) or (ii)(b) administered to a subject alone.

[0425] In some embodiments, the subject receives 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 fewer doses of (ii)(a) or (ii)(b) than the number of doses of (ii)(a) or (ii)(b) administered to a subject alone.

[0426] In some embodiments, the pharmaceutical composition of (i) is co-formulated with the pharmaceutical composition of (ii).

[0427] In some embodiments, the pharmaceutical composition of (i) is formulated separately from the pharmaceutical composition of (ii).

[0428] In some embodiments, the pharmaceutical composition of (i) is administered separately from the pharmaceutical composition of (ii).

[0429] Provided herein is a method of treating or preventing an infection by a virus or treating a respiratory disease or condition associated with an infection by a virus comprising administering to a subject in need thereof: (i) a pharmaceutical composition comprising (a) a polypeptide comprising at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); or (b) a polynucleotide encoding a polypeptide comprising at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and (ii) a pharmaceutical composition comprising (a) a polypeptide having an amino acid sequence of a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; (b) a recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; or a 2019 SARS-CoV 2 spike protein pharmaceutical composition comprising (ii)(a) or (ii)(b); wherein the subject receives a dose of (i)(a) or (i)(b) that is lower than a dose of (i)(a) or (i)(b) administered to a subject alone.

[0430] Provided herein is a method of treating or preventing an infection by a virus or treating a respiratory disease or condition associated with an infection by a virus comprising administering to a subject in need thereof: (i) a pharmaceutical composition comprising (a) a polypeptide comprising at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); or (b) a polynucleotide encoding a polypeptide comprising at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and (ii) a pharmaceutical composition comprising (a) a polypeptide having an amino acid sequence of a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; (b) a recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; or a 2019 SARS-CoV 2 spike protein pharmaceutical composition comprising (ii)(a) or (ii)(b); wherein the subject receives a number of doses of (i)(a) or (i)(b) that is lower than a number of doses of (i)(a) or (i)(b) administered to a subject alone.

[0431] In some embodiments, the subject receives a dose of (i)(a) or (i)(b) that is at least 1.1, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 times lower than a dose of (i)(a) or (i)(b) administered to a subject alone.

[0432] In some embodiments, the subject receives 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 fewer doses of (i)(a) or (i)(b) than the number of doses of (i)(a) or (i)(b) administered to a subject alone.

[0433] In some embodiments, the pharmaceutical composition of (i) is co-formulated with the pharmaceutical composition of (ii).

[0434] In some embodiments, the pharmaceutical composition of (i) is formulated separately from the pharmaceutical composition of (ii).

[0435] In some embodiments, the pharmaceutical composition of (i) is administered separately from the pharmaceutical composition of (ii).

[0436] In some embodiments, the pharmaceutical composition is a coformulation.

[0437] In some embodiments, the first pharmaceutical composition is administered with or on the same day as the second pharmaceutical composition.

[0438] In some embodiments, the first pharmaceutical composition is administered simultaneously with the second pharmaceutical composition.

[0439] In some embodiments, the first pharmaceutical composition is administered at a first location of the subject and the second pharmaceutical composition is administered at a second location of the subject that is different than the first location.

[0440] In some embodiments, the first location is at an appendage of the subject and second location is at an opposing appendage of the subject,

[0441] In some embodiments, the first appendage is an arm and the second appendage is an arm.

[0442] In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are administered to the same location of the subject.

[0443] In some embodiments, the pharmaceutical composition is administered at a first time point and a second time point, wherein the second time point is at least about, at most about or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 days after the first time point; at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 weeks after the first time point; or at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 months after the first time point.

[0444] In some embodiments, the pharmaceutical composition is administered at a third time point, wherein the third time point is at least about, at most about or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 days after the second time point; at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 weeks after the second time point; or at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 months after the second time point.

[0445] In some embodiments, the third time point is at least about, at most about or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 days after the first time point; at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 weeks after the first time point; or at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 months after the first time point.

[0446] In some embodiments, the first pharmaceutical composition is administered at a first time point and a second time point, wherein the second time point is at least about, at most about or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 days after the first time point; at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 weeks after the first time point; or at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 months after the first time point.

[0447] In some embodiments, the first pharmaceutical composition is administered at a third time point, wherein the third time point is at least about, at most about or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 days after the second time point; at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 weeks after the second time point; or at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 months after the second time point.

[0448] In some embodiments, the third time point is at least about, at most about or about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 days after the first time point; at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 weeks after the first time point; or at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 months after the first time point.

[0449] In some embodiments, the second pharmaceutical composition is administered at the first time point.

[0450] In some embodiments, the second pharmaceutical composition is administered at the second time point.

[0451] In some embodiments, the second pharmaceutical composition is administered at the third time point.

[0452] In some embodiments, the second pharmaceutical composition is administered at least about, at most about or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 days after the first time point; at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 weeks after the first time point; or at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 months after the first time point.

[0453] In some embodiments, the second pharmaceutical composition is administered at least about, at most about or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 days after the second time point; at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 weeks after the second time point; or at least about, at most about or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 months after the second time point.

[0454] Provided herein is a method of treating or preventing an infection by a virus or treating a respiratory disease or condition associated with an infection by a virus comprising administering to a subject in need thereof: (i) a pharmaceutical composition comprising (a) a polypeptide comprising at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); or (b) a polynucleotide encoding a polypeptide comprising at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); wherein the pharmaceutical composition is administered at a first time point and a second time point, wherein the second time point is at least about 2 days after the first time point.

[0455] In some embodiments, the pharmaceutical composition is administered at a third time point, wherein the third time point is at least about 2 days after the second time point.

[0456] In some embodiments, the second time point is at least about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days after the first time point, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 weeks after the first time point, or at least about 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 months after the first time point.

[0457] In some embodiments, the second time point is at most about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days after the first time point, at most about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 weeks after the first time point, or at most about 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 months after the first time point.

[0458] In some embodiments, the second time point is about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days after the first time point, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 weeks after the first time point, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 months after the first time point.

[0459] In some embodiments, the third time point is at least about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days after the second time point, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 weeks after the second time point, or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 months after the second time point.

[0460] In some embodiments, the third time point is at most about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days after the second time point, at most about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 weeks after the second time point, or at most about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 months after the second time point.

[0461] In some embodiments, the third time point is about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35 days after the second time point, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 weeks after the second time point, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 months after the second time point.

[0462] In some embodiments, the third time point is at least about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 days after the first time point, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 weeks after the first time point, or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 months after the first time point.

[0463] In some embodiments, the third time point is at most about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 days after the first time point, at most about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 weeks after the first time point, or at most about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 months after the first time point.

[0464] In some embodiments, the third time point about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 days after the first time point, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 weeks after the first time point, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 months after the first time point.

[0465] In some embodiments, the method further comprises administering to the subject: (ii)(a) a polypeptide having an amino acid sequence of a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; (b) a recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; or a 2019 SARS-CoV 2 spike protein pharmaceutical composition comprising (ii)(a) or (ii)(b).

[0466] In some embodiments, the subject has an immunodeficiency.

[0467] In some embodiments, the subject has a B cell immunodeficiency.

[0468] In some embodiments, the pharmaceutical composition is administered prophylactically.

[0469] Provided herein is a pharmaceutical composition comprising: (i) a recombinant polynucleotide encoding a polypeptide comprising at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and (ii) a recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof.

[0470] In some embodiments, the ratio (e.g., mass ratio) of (i):(ii) is from 20:1 to 1:20.

[0471] In some embodiments, the ratio (e.g., mass ratio) of (i):(ii) is less than 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1 or 100:1.

[0472] In some embodiments, the ratio (e.g., mass ratio) of (i):(ii) is greater than 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90 or 1:100.

[0473] Provided herein is a composition comprising: (i) a first pharmaceutical composition comprising a first recombinant polynucleotide encoding a polypeptide comprising at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and (ii) a second pharmaceutical composition comprising a second recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof.

[0474] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is from 1:50 to 50:1.

[0475] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is from about 1:25 to 25:1.

[0476] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is from about 1:10 to 10:1.

[0477] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is about 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 1:9.5, 1:8.5, 1:7.5, 1:6.5, 1:5.5, 1:4.5, 1:3.5, 1:2.5, 1:1.5, 2.5:1, 3.5:1, 4.5:1, 5.5:1, 6.5:1, 7.5:1, 8.5:1, 9.5:1, 2:9, 2:8, 2:7, 2:6, 2:5, 2:4, 2:3, 3:2, 4:2, 5:2, 6:2, 7:2, 8:2, 9:2, 3:8, 3:7, 3:5, 3:4, 4:3, 5:3, 7:3, 8:3, 4:9, 4:7, 4:5, 5:4, 7:4, 9:4, 5:9, 5:8, 5:7, 5:6, 6:5, 7:5, 8:5, 9:5, 6:7, 7:6, 7:8, 8:7, 8:9 or 9:8.

[0478] Provided herein is a pharmaceutical composition comprising: (i) a first recombinant polynucleotide encoding a polypeptide comprising at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and (ii) a second recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof.

[0479] In some embodiments, the pharmaceutical composition comprises a nanoparticle, wherein the nanoparticle comprises the first recombinant polynucleotide and the second recombinant polynucleotide.

[0480] In some embodiments, the nanoparticle is present in the pharmaceutical composition at a dose of from 100 ng to 500 micrograms.

[0481] In some embodiments, the nanoparticle is present in the pharmaceutical composition at a dose of from 1 microgram to 100 micrograms.

[0482] In some embodiments, the nanoparticle is present in the pharmaceutical composition at a dose of from 1 microgram to 30 micrograms, 5 micrograms to 40 micrograms or 10 microgram to 50 micrograms.

[0483] In some embodiments, the nanoparticle is present in the pharmaceutical composition at a dose of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1,000 micrograms.

[0484] In some embodiments, the ratio (e.g., mass ratio) of the first recombinant polynucleotide to the second recombinant polynucleotide is from about 1:50 to 50:1.

[0485] In some embodiments, the ratio (e.g., mass ratio) of the first recombinant polynucleotide to the second recombinant polynucleotide is from about 1:25 to 25:1.

[0486] In some embodiments, the ratio (e.g., mass ratio) of the first recombinant polynucleotide to the second recombinant polynucleotide is from about 1:10 to 10:1.

[0487] In some embodiments, the ratio (e.g., mass ratio) of the first recombinant polynucleotide to the second recombinant polynucleotide is about 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 1:9.5, 1:8.5, 1:7.5, 1:6.5, 1:5.5, 1:4.5, 1:3.5, 1:2.5, 1:1.5, 2.5:1, 3.5:1, 4.5:1, 5.5:1, 6.5:1, 7.5:1, 8.5:1, 9.5:1, 2:9, 2:8, 2:7, 2:6, 2:5, 2:4, 2:3, 3:2, 4:2, 5:2, 6:2, 7:2, 8:2, 9:2, 3:8, 3:7, 3:5, 3:4, 4:3, 5:3, 7:3, 8:3, 4:9, 4:7, 4:5, 5:4, 7:4, 9:4, 5:9, 5:8, 5:7, 5:6, 6:5, 7:5, 8:5, 9:5, 6:7, 7:6, 7:8, 8:7, 8:9 or 9:8.

[0488] Provided herein is a composition comprising: (i) a first pharmaceutical composition comprising a recombinant polynucleotide encoding a polypeptide comprising at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and (ii) a second pharmaceutical composition comprising a recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof.

[0489] In some embodiments, the first pharmaceutical composition comprises a first nanoparticle, wherein the first nanoparticle comprises the recombinant polynucleotide encoding a polypeptide comprising at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and wherein the second pharmaceutical composition comprises a second nanoparticle, wherein the second nanoparticle comprises the recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof.

[0490] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is from about 1:50 to 50:1.

[0491] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is from about 1:25 to 25:1.

[0492] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is from about 1:10 to 10:1.

[0493] In some embodiments, the ratio (e.g., mass ratio) of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is about 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 1:9.5, 1:8.5, 1:7.5, 1:6.5, 1:5.5, 1:4.5, 1:3.5, 1:2.5, 1:1.5, 2.5:1, 3.5:1, 4.5:1, 5.5:1, 6.5:1, 7.5:1, 8.5:1, 9.5:1, 2:9, 2:8, 2:7, 2:6, 2:5, 2:4, 2:3, 3:2, 4:2, 5:2, 6:2, 7:2, 8:2, 9:2, 3:8, 3:7, 3:5, 3:4, 4:3, 5:3, 7:3, 8:3, 4:9, 4:7, 4:5, 5:4, 7:4, 9:4, 5:9, 5:8, 5:7, 5:6, 6:5, 7:5, 8:5, 9:5, 6:7, 7:6, 7:8, 8:7, 8:9 or 9:8.

[0494] In some embodiments, the first nanoparticle is present in the first pharmaceutical composition at a dose of from about 100 ng to 500 micrograms.

[0495] In some embodiments, the first nanoparticle is present in the first pharmaceutical composition at a dose of from about 1 microgram to 100 micrograms.

[0496] In some embodiments, the first nanoparticle is present in the first pharmaceutical composition at a dose of from about 1 microgram to 30 micrograms, 5 micrograms to 40 micrograms or 10 microgram to 50 micrograms.

[0497] In some embodiments, the first nanoparticle is present in the first pharmaceutical composition at a dose of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1,000 micrograms.

[0498] In some embodiments, the second nanoparticle is present in the second pharmaceutical composition at a dose of from about 100 ng to 500 micrograms.

[0499] In some embodiments, the second nanoparticle is present in the second pharmaceutical composition at a dose of from about 1 microgram to 100 micrograms.

[0500] In some embodiments, the second nanoparticle is present in the second pharmaceutical composition at a dose of from about 1 microgram to 30 micrograms, 5 micrograms to 40 micrograms or 10 microgram to 50 micrograms.

[0501] In some embodiments, the second nanoparticle is present in the second pharmaceutical composition at a dose of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1,000 micrograms.

[0502] In some embodiments, the recombinant polynucleotide in (i) is present in the first pharmaceutical composition at a dose of from about 50 ng to 250 micrograms.

[0503] In some embodiments, the recombinant polynucleotide in (i) is present in the first pharmaceutical composition at a dose of from about 0.5 to 50 micrograms.

[0504] In some embodiments, the recombinant polynucleotide in (i) is present in the first pharmaceutical composition at a dose of from about 0.5 microgram to 15 micrograms, 2.5 micrograms to 20 micrograms or 5 microgram to 25 micrograms.

[0505] In some embodiments, the recombinant polynucleotide in (i) is present in the first pharmaceutical composition at a dose of about 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450 or 500 micrograms.

[0506] In some embodiments, the recombinant polynucleotide in (ii) is present in the second pharmaceutical composition at a dose of from about 50 ng to 250 micrograms.

[0507] In some embodiments, the recombinant polynucleotide in (ii) is present in the second pharmaceutical composition at a dose of from about 0.5 to 50 micrograms.

[0508] In some embodiments, the recombinant polynucleotide in (ii) is present in the second pharmaceutical composition at a dose of from about 0.5 microgram to 15 micrograms, 2.5 micrograms to 20 micrograms or 5 microgram to 25 micrograms.

[0509] In some embodiments, the recombinant polynucleotide in (ii) is present in the second pharmaceutical composition at a dose of about 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450 or 500 micrograms.

[0510] In some embodiments, the nanoparticle is a lipid nanoparticle.

[0511] Provided herein is a composition comprising: (i) a polypeptide comprising at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, (b) a sequence comprising an epitope sequence from membrane glycoprotein (M) and (c) a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); (ii) a polynucleotide encoding a polypeptide, wherein the polypeptide comprises at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, (b) a sequence comprising an epitope sequence from membrane glycoprotein (M) and (c) a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); (iii) a T cell receptor (TCR) or a T cell comprising the TCR, wherein the TCR binds to an epitope sequence of the polypeptide in complex with a corresponding HLA class I or class II molecule; (iv) an antigen presenting cell comprising (i) or (ii); or (v) an antibody or B cell comprising the antibody, wherein the antibody binds to an epitope sequence of the polypeptide; and a pharmaceutically acceptable excipient.

[0512] In some embodiments, the polypeptide comprises (a) a sequence comprising an epitope sequence from ORF1ab, (b) a sequence comprising an epitope sequence from membrane glycoprotein (M) and (c) a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N). In some embodiments, the sequence comprising an epitope sequence from ORF1ab is C-terminal to the sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N). In some embodiments, the sequence comprising an epitope sequence from ORF1ab is N-terminal to the sequence comprising an epitope sequence from membrane glycoprotein (M). In some embodiments, the sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N) is N-terminal to the sequence comprising an epitope sequence from membrane glycoprotein (M).

[0513] In some embodiments, the polypeptide comprises at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, (b) a sequence comprising an epitope sequence from membrane glycoprotein (M) and (c) a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N)

[0514] In some embodiments, the polypeptide comprises (a) 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more epitope sequence from ORF1ab, (b) a sequence comprising an epitope sequence from membrane glycoprotein (M) and (c) a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N).

[0515] In some embodiments, the epitope sequence from ORF1ab is an epitope sequence from a non-structural protein. In some embodiments, the non-structural protein is selected from the group consisting of NSP1, NSP2, NSP3, NSP4 and combinations thereof. In some embodiments, the polypeptide comprises a sequence comprising an epitope sequence from NSP1, a sequence comprising an epitope sequence from NSP2, a sequence comprising an epitope sequence from NSP3 and a sequence comprising an epitope sequence from NSP4.

[0516] In some embodiments, the epitope sequence from ORF1ab is selected from the group consisting of YLFDESGEFKL, YLFDESGEF, FGDDTVIEV, QLMCQPILL, TTDPSFLGRY, PTDNYITTY, PSFLGRY, AEAELAKNV, KTIQPRVEK and any combination thereof.

[0517] In some embodiments, the epitope sequence from nucleocapsid glycoprotein (N) is LLLDRLNQL. In some embodiments, the epitope sequence from membrane phosphoprotein (M) is VATSRTLSY. In some embodiments, the polypeptide comprises an epitope sequence from nucleocapsid glycoprotein (N) that is LLLDRLNQL and an epitope sequence from membrane phosphoprotein (M) that is VATSRTLSY.

[0518] In some embodiments, the polypeptide comprises (a) each of the following epitope sequences from ORF1ab: YLFDESGEFKL, YLFDESGEF, FGDDTVIEV, QLMCQPILL, TTDPSFLGRY, PTDNYITTY, PSFLGRY, AEAELAKNV, KTIQPRVEK; (b) an epitope sequence from nucleocapsid glycoprotein (N) that is LLLDRLNQL; and (c) an epitope sequence from membrane phosphoprotein (M) that is VATSRTLSY.

[0519] In some embodiments, the sequence comprising an epitope sequence from ORF1ab is selected from the group consisting of the following sequences or fragments thereof:MVTNNTFTLKVPHVGEIPVAYRKVLLKTIQPRVEKYLFDESGEFKLSEVGPEHSLAEYYIFFASFYY; MVTNNTFTLKVPHVGEIPVAYRKVLLKTIQPRVEKYLFDESGEFKLSEVGPEHSLAEY; APKEIIFLEGETLFGDDTVIE VAIILASFSAST; APKEIIFLEGETLFGDDTVIEV; HTTDPSFLGRYMSALFADDLNQLTGYHTDFSSEIIGYQLMCQPILLAEAELAKNVSLILGTVSWNL; TTDPSFLGRYMSALFADDLNQLTGYHTDFSSEIIGYQLMCQPILLAEAELAKNVSLILGTVSWNL; LLSAGIFGAITDVFYKENSYKVPTDNYITTY; and combinations thereof.

[0520] In some embodiments, the sequence comprising an epitope sequence from membrane glycoprotein (M) is selected from the group consisting of the following sequences or fragments thereof:ADSNGTITVEELKKLLEQWNLVIGFLFLTWICLLQFAYANRNRFLYIIKLIFLWLLWPVTLACFVLAAVYRINWITGGIAIAMACLVGLMWLSYFIASFRLFARTRSMWSFNPETNILLNVPLHGTILTRPLLESELVIGAVILRGHLRIAGHHLGRCDIKDLPKEITVATSRTLSYYKLGASQRVAGDSGFAAYSRYRIGNYKLNTDHSSSSDNIALLVQ; FAYANRNRFLYIIKLIFLWLLWPVTLACFVLAAVYRINWITGGIAIAMACLVGLMWLSYFIASFRLF; LGRCDIKDLPKEITVATSRTLSYYKLGASQRVA; KLLEQWNLVIGF; NRNRFLYIIKLIFLWLLWPVTLACFVLAAVY; SELVIGAVILRGHLRIAGHHLGR; VATSRTLSYYKLGASQRV; GLMWLSYF; and combinationsthereof.

[0521] In some embodiments, the sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N) is selected from the group consisting of the following sequences or fragments thereof:KDLSPRWYFYYLGTGPEAGLPYGANKDGIIWVATEGALNTPKDHIGTRNPANNAAIVLQLPQGTTLPKGFYAEGSRGGSQASSRSSSRSRNSSRNSTPGSSRGTSPARMAGNGGDAALALLLLDRLNQLESKMSGKGQQQQGQTVTKKSAAEASKKPRQKRTATKAYNVTQAFGRRGPEQTQGNFGDQELIRQGTDYKHWPQIAQFAPSASAFFGMSRIGMEVTPSGTWLTYTGAIKLDDKDPNFKDQVILLNKHIDAYKTFPPTEPKKDKKKKADETQALPQRQKKQQTVTLLPAADLDDFSKQLQQSMSSADSTQA;RMAGNGGDAALALLLLDRLNQLESKMSGKGQQQ;YKHWPQIAQFAPSASAFFGMSRIGMEVTPSGTWLTYTGAIKLDDKDPNFKDQVILLNKHIDAYKTFP;SPARMAGNGGDAALALLLLDRLNQLESKM SGKGQQQQGQTVTKKSAAEASKKPRQKRTATKAYNVTQAFGRRGPEQTQGNFGDQELIRQGTDYKHWPQIAQFAPSASAFFGMSRIGMEVTPSGTWLTYTGAIKLDDKDPNFKDQVILLNKHIDAYKTFPPTEPKKDK and combinations thereof.

[0522] In some embodiments, the polypeptide comprises one or more linker sequences. In some embodiments, the one or more linker sequences are selected from the group consisting of GGSGGGGSGG, GGSLGGGGSG. In some embodiments, the one or more linker sequences comprise cleavage sequences. In some embodiments, the one or more cleavage sequences are selected from the group consisting of FRAC, KRCF, KKRY, ARMA, RRSG, MRAC, KMCG, ARCA, KKQG, YRSY, SFMN, FKAA, KRNG, YNSF, KKNG, RRRG, KRYS, and ARYA.

[0523] In some embodiments, the polypeptide comprises a transmembrane domain sequence. In some embodiments, the transmembrane sequence is C-terminal to the sequence comprising an epitope sequence from ORF1ab, the sequence comprising an epitope sequence from membrane glycoprotein (M) and the sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N). In some embodiments, the is transmembrane sequence EQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKL HYT.

[0524] In some embodiments, the polypeptide comprises an SEC sequence. In some embodiments, the SEC sequence is N-terminal to the sequence comprising an epitope sequence from ORF1ab, the sequence comprising an epitope sequence from membrane glycoprotein (M) and the sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N). In some embodiments, the SEC sequence is MFVFLVLLPLVSSQCVNLT.

[0525] In some embodiments, the composition comprises the polynucleotide encoding the polypeptide. In some embodiments, the polynucleotide is an mRNA. In some embodiments, the polynucleotide comprises a codon optimized sequence for expression in a human.

[0526] In some embodiments, the polynucleotide comprises a dEarI-hAg sequence. In some embodiments, the dEarI-hAg sequence is ATTCTTCTGGTCCCCACAGACTCAGAGAGAACCC, optionally wherein each T is a U.

[0527] In some embodiments, the polynucleotide comprises a Kozak sequence. In some embodiments, the a Kozak sequences is GCCACC.

[0528] In some embodiments, the polynucleotide comprises an F element sequence. In some embodiments, the F element sequence is a 3 UTR of amino-terminal enhancer of split (AES). In some embodiments, the F element sequence is CTGGTACTGCATGCACGCAATGCTAGCTGCCCCTTTCCCGTCCTGGGTACCCCGAGTCTCCC CCGACCTCGGGTCCCAGGTATGCTCCCACCTCCACCTGCCCCACTCACCACCTCTGCTAGTTC CAGACACCTCC, optionally wherein each T is a U.

[0529] In some embodiments, the polynucleotide comprises an I element sequence. In some embodiments, the I element sequence is a 3′ UTR of mitochondrially encoded 12S rRNA (mtRNR1). In some embodiments, the I element sequence is CAAGCACGCAGCAATGCAGCTCAAAACGCTTAGCCTAGCCACACCCCCACGGGAAACAGCA GTGATTAACCTTTAGCAATAAACGAAAGTTTAACTAAGCTATACTAACCCCAGGGTTGGTCA ATTTCGTGCCAGCCACACC, optionally wherein each T is a U.

[0530] In some embodiments, the polynucleotide comprises a poly A sequence. In some embodiments, the poly A sequence is AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAGCATATGACTAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA, optionally wherein each T is a U.

[0531] In some embodiments, each of the epitope sequences from the ORF1ab, the membrane glycoprotein, and the nucleocapsid phosphoprotein are from 2019 SARS-CoV-2.

[0532] In some embodiments, one or more or each epitope elicits a T cell response.

[0533] In some embodiments, one or more or each epitope has been observed by mass spectrometry as being presented by an HLA molecule.

[0534] In some embodiments, the composition comprises (i) a polypeptide with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence selected from the group consisting of RS C1p1full, RS C2p1full, RS C3p1full, RS C4p1full, RS C5p1, RS C5p2, RS C5p2full, RS C6p1, RS C6p2, RS C6p2full, RS C7p1, RS C7p2, RS C7p2full, RS C7p4, RS C7p4full, RS C8p1, RS C8p2 and RS C8p2full; (ii) a polynucleotide encoding a polypeptide with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence selected from the group consisting of RS C1p1full, RS C2p1full, RS C3p1full, RS C4p1full, RS C5p1, RS C5p2, RS C5p2full, RS C6p1, RS C6p2, RS C6p2full, RS C7p1, RS C7p2, RS C7p2full, RS C7p4, RS C7p4full, RS C8p1, RS C8p2 and RS C8p2full; or (iii) a polynucleotide with at least at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: RS C1n1, RS C2n1, RS C3n1, RS C4n1, RS C5n1, RS Con1, RS C7n1, RS C8n1, RS C5n2, RS Con2, RS C7n2, RS C8n2, RS C5n2full, RS Con2full, RS C7n2full, RS C8n2full, RS C7n4, RS C7n4full.

[0535] Also provided herein is a pharmaceutical composition comprising any of the compositions described herein.

[0536] Also provided herein is a pharmaceutical composition comprising: (i) a polypeptide comprising an epitope sequence of Table 1A, Table 1B, Table 1C, Table 2Ai, Table 2Aii, Table 2B and / or Table 16; (ii) a polynucleotide encoding the polypeptide; (iii) a T cell receptor (TCR) or a T cell comprising the TCR, wherein the TCR binds to the epitope sequence in complex with a corresponding HLA class I or class II molecule; (iv) an antigen presenting cell comprising (i) or (ii); or (v) an antibody or B cell comprising the antibody, wherein the antibody binds to the epitope sequence; and a pharmaceutically acceptable excipient.

[0537] In some embodiments, the epitope sequence comprises one or more or each of the following: YLFDESGEFKL, YLFDESGEF, FGDDTVIEV, LLLDRLNQL, QLMCQPILL, TTDPSFLGRY, PTDNYITTY, PSFLGRY, AEAELAKNV, VATSRTLSY and KTIQPRVEK. In some embodiments, the epitope sequence comprises one or more or each of the following: SAPPAQYEL, AVASKILGL, EYADVFHLY, DEFTPFDVV, VRIQPGQTF, SFRLFARTR, KFLPFQQF, VVQEGVLTA, RLDKVEAEV, FGADPIHSL, NYNYLYRLF, KYIKWPWYI, KWPWYIWLGF, LPFNDGVYF, QPTESIVRF, IPFAMQMAY, YLOPRTFLL and RLQSLQTYV.

[0538] In some embodiments, the epitope sequence is from an orflab protein. In some embodiments, the epitope sequence is from an orfla protein In some embodiments, the epitope sequence is from a surface glycoprotein(S) or a shifted reading frame thereof. In some embodiments, the epitope sequence is from a nucleocapsid phosphoprotein (N). In some embodiments, the epitope sequence is from an ORF3a protein. In some embodiments, the epitope sequence is from a membrane glycoprotein (M). In some embodiments, the epitope sequence is from an ORF7a protein. In some embodiments, the epitope sequence is from an ORF8 protein. In some embodiments, the epitope sequence is from an envelope protein (E). In some embodiments, the epitope sequence is from an ORF6 protein. In some embodiments, the epitope sequence is from an ORF7b protein. In some embodiments, the epitope sequence is from an ORF10 protein. In some embodiments, the epitope sequence is from an ORF9b protein.

[0539] Also provided herein is a pharmaceutical composition comprising: a polypeptide having an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of any one of the sequences depicted in column 2 of Table 11, column 2 of Table 12 or column 3 of Table 15; or a recombinant polynucleotide encoding a polypeptide having an amino acid sequence with at least at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of any one of the sequences depicted in column 2 of Table 11, column 2 of Table 12 or column 3 of Table 15.

[0540] In some embodiments, the pharmaceutical composition comprises a polypeptide with at least at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence selected from the group consisting of RS C1p1full, RS C2p1full, RS C3p1full, RS C4p1full, RS C5p1, RS C5p2, RS C5p2full, RS C6p1, RS C6p2, RS C6p2full, RS C7p1, RS C7p2, RS C7p2full, RS C7p4, RS C7p4full, RS C8p1, RS C8p2 and RS C8p2full; or a polynucleotide encoding a polypeptide with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence selected from the group consisting of RS Clp1full, RS C2p1full, RS C3p1full, RS C4p1full, RS C5p1, RS C5p2, RS C5p2full, RS C6p1, RS C6p2, RS C6p2full, RS C7p1, RS C7p2, RS C7p2full, RS C7p4, RS C7p4full, RS C8p1, RS C8p2 and RS C8p2full. In some embodiments, the pharmaceutical composition comprises a polynucleotide with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: RS C1n1, RS C2n1, RS C3n1, RS C4n1, RS C5n1, RS Con1, RS C7n1, RS C8n1, RS C5n2, RS C6n2, RS C7n2, RS C8n2, RS C5n2full, RS Con2full, RS C7n2full, RS C8n2full, RS C7n4 and RS C7n4full,.

[0541] In some embodiments, the polynucleotide is an mRNA.

[0542] In some embodiments, the pharmaceutical composition further comprises one or more lipid components. In some embodiments, the one or more lipids comprise a lipid nanoparticle (LNP). In some embodiments, the LNP encapsulates the recombinant polynucleotide construct.

[0543] In some embodiments, the polypeptide is synthetic. In some embodiments, the polypeptide is recombinant.

[0544] In some embodiments, the polypeptide is from 8-1000 amino acids in length.

[0545] In some embodiments, the epitope sequence binds to or is predicted to bind to an HLA class I or class II molecule with a KD of 1000 nM or less. In some embodiments, the epitope sequence binds to or is predicted to bind to an HLA class I or class II molecule with a KD of 500 nM or less.

[0546] In some embodiments, the epitope sequence comprises a sequence of a viral protein expressed by a virus-infected cell of a subject.

[0547] Also provided herein is a method of treating or preventing an infection by a virus or treating a respiratory disease or condition associated with an infection by a virus comprising administering to a subject in need thereof a pharmaceutical composition described herein.

[0548] In some embodiments, the virus is a coronavirus. In some embodiments, the virus is 2019 SARS-CoV 2. In some embodiments, an HLA molecule expressed by the subject is unknown at the time of administration. In some embodiments, the ability of the virus to avoid escape of recognition by an immune system of the subject is less compared to the ability of the virus to avoid escape of recognition by an immune system of a subject administered a pharmaceutical composition containing an epitope from a single protein or epitopes from fewer proteins than in a pharmaceutical composition described herein. In some embodiments, the subject express an HLA molecule encoded by an HLA allele of any one of Table 1A, Table 1B, Table 1C, Table 2Ai or Table 2Aii, Table 2B or Table 16 and the epitope sequence is an HLA allele-matched epitope sequence.

[0549] In some embodiments, the epitope sequence comprises one or more or each of the following: SAPPAQYEL, AVASKILGL, EYADVFHLY, DEFTPFDVV, VRIQPGQTF, SFRLFARTR, KFLPFQQF, VVQEGVLTA, RLDKVEAEV and FGADPIHSL.

[0550] Also provided herein is a method of treating or preventing a 2019 SARS-CoV 2 infection in a subject in need thereof, comprising administering to the subject a pharmaceutical composition described herein.

[0551] In some embodiments, the pharmaceutical composition is administered in addition to one or more therapeutics for the 2019 SARS-CoV 2 viral infection in the subject. In some embodiments, the pharmaceutical composition is administered in combination with (a) a polypeptide having an amino acid sequence of a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; (b) a recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof; or a 2019 SARS-CoV 2 spike protein pharmaceutical composition comprising (a) or (b). In some embodiments, the 2019 SARS-CoV 2 spike protein or a variant or fragment thereof is a SARS-CoV-2 spike protein or a fragment thereof.

[0552] In some embodiments, the pharmaceutical composition is administered 1-10 weeks after a first administration of the 2019 SARS-CoV 2 spike protein pharmaceutical composition. In some embodiments, the pharmaceutical composition is administered 1-6 weeks, 1-6 months or 1-2 years or later after a first administration of the 2019 SARS-CoV 2 spike protein pharmaceutical composition. In some embodiments, the pharmaceutical composition is administered on the same day or simultaneously with an administration of the 2019 SARS-CoV 2 spike protein pharmaceutical composition. In some embodiments, the pharmaceutical composition is co-formulated with the polypeptide having an amino acid sequence of a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof or the recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof. In some embodiments, the pharmaceutical composition is administered before an administration of the 2019 SARS-CoV 2 spike protein pharmaceutical composition, such as 2-10 weeks before an administration of the 2019 SARS-CoV 2 spike protein pharmaceutical composition. In some embodiments, the pharmaceutical composition is administered prophylactically. In some embodiments, the pharmaceutical composition is administered once every 1, 2, 3, 4, 5, 6 or more weeks; or once every 1-7, 7-14, 14-21, 21-28, or 28-35 days; or once every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days.

[0553] Also provided herein is a use of a composition described herein for preparing a therapeutic for treating or preventing a respiratory viral infection caused by 2019 SARS CoV-2 virus.

[0554] Also provided herein is a composition described herein or a pharmaceutical composition described herein for use as a medicament.

[0555] Also provided herein is a composition described herein or a pharmaceutical composition described herein for use in the treatment or prevention of a respiratory viral infection caused by 2019 SARS CoV-2 virus.

[0556] Provided herein is an antigenic peptide comprising an epitope sequence from Table 1A, Table 1B, Table 1C, Table 2Ai, Table 2Aii or Table 2B. Also provided herein is a polynucleotide encoding and antigenic peptide comprising an epitope sequence from Table 1A, Table 1B, Table 1C, Table 2Ai, Table 2Aii or Table 2B. The antigenic peptide and / or polynucleotide may be recombinant. The antigenic peptide and / or polynucleotide may be isolated or purified. The antigenic peptide may be synthetic or expressed from a polynucleotide.

[0557] Also provided herein is an antibody or B cell comprising an antibody that binds to an antigenic peptide comprising an epitope sequence from Table 1A, Table 1B, Table 1C, Table 2Ai, Table 2Aii or Table 2B.

[0558] Also provided herein is a T cell receptor (TCR) or T cell comprising a TCR that binds an epitope sequence from Table 1A or Table 1B in complex with a corresponding MHC class I molecule according to Table 1A or Table 1B. For example, the TCR can bind to an epitope sequence from column 2 (set 1) of Table 1A in complex with a corresponding MHC class I molecule from column 3 (set 1) in the same row of Table 1A. For example, the TCR can bind to an epitope sequence from column 4 (set 2) of Table 1A in complex with a corresponding MHC class I molecule from column 5 (set 2) in the same row of Table 1A. For example, the TCR can bind to an epitope sequence from column 6 (set 3) of Table 1A in complex with a corresponding MHC class I molecule from column 7 (set 3) in the same row of Table 1A. For example, the TCR can bind to an epitope sequence from column 2 (set 1) of Table 1B in complex with a corresponding MHC class I molecule from column 3 (set 1) in the same row of Table 1B. For example, the TCR can bind to an epitope sequence from column 4 (set 2) of Table 1B in complex with a corresponding MHC class I molecule from column 5 (set 2) in the same row of Table 1B.

[0559] Also provided herein is a T cell receptor (TCR) or T cell comprising a TCR that binds to an epitope sequence from Table 2Ai or Table 2Aii in complex with a corresponding MHC class II molecule according to Table 2Ai or Table 2Aii. For example, the TCR can bind to an epitope sequence from column 2 (set 1) of Table 2Ai in complex with a corresponding MHC class II molecule from column 3 (set 1) in the same row of Table 2Ai. For example, the TCR can bind to an epitope sequence from column 4 (set 2) of Table 2Ai in complex with a corresponding MHC class II molecule from column 5 (set 2) in the same row of Table 2Ai. Likewise, a TCR can bind to an epitope sequence from the left column of Table 2Aii in complex with a corresponding MHC class II molecule from the right column of Table 2Aii.

[0560] Provided herein is a method of treating or preventing viral infection in a subject in need thereof comprising administering to the subject an antigenic peptide comprising an epitope sequence from Table 1A, Table 1B, Table 1C, Table 2Ai, Table 2Aii or Table 2B. Also provided herein is a method of treating or preventing viral infection in a subject in need thereof comprising administering to the subject a polynucleotide encoding and antigenic peptide comprising an epitope sequence from Table 1A, Table 1B, Table 1C, Table 2Ai, Table 2Aii or Table 2B.

[0561] Also provided herein is a method of treating or preventing a viral infection in a subject in need thereof comprising administering to the subject an antibody or B cell comprising an antibody that binds to an antigenic peptide comprising an epitope sequence from Table 1A, Table 1B, Table 1C, Table 2Ai, Table 2Aii or Table 2B.

[0562] Also provided herein is a method of treating or preventing viral infection in a subject in need thereof comprising administering to the subject a T cell receptor (TCR) or T cell comprising a TCR that that binds an epitope sequence from Table 1A or Table 1B in complex with a corresponding MHC class I molecule according to Table 1A or Table 1B.

[0563] For example, the method can comprise administering to the subject a TCR or T cell comprising a TCR that can bind to an epitope sequence from column 2 (set 1) of Table 1A in complex with a corresponding MHC class I molecule from column 3 (set 1) in the same row of Table 1A. For example, the method can comprise administering to a TCR or T cell comprising a TCR that can bind to an epitope sequence from column 2 (set 1) of Table 1A in complex with a corresponding MHC class I molecule from column 3 (set 1) in the same row of Table 1A to a subject that expresses the corresponding MHC class I molecule from column 3 (set 1). For example, the method can comprise administering to the subject a TCR or T cell comprising a TCR that can bind to an epitope sequence from column 4 (set 2) of Table 1A in complex with a corresponding MHC class I molecule from column 5 (set 2) in the same row of Table 1A. For example, the method can comprise administering to a TCR or T cell comprising a TCR that can bind to an epitope sequence from column 4 (set 2) of Table 1A in complex with a corresponding MHC class I molecule from column 5 (set 2) in the same row of Table 1A to a subject that expresses the corresponding MHC class I molecule from column 5 (set 2). For example, the method can comprise administering to the subject a TCR or T cell comprising a TCR that can bind to an epitope sequence from column 6 (set 3) of Table 1A in complex with a corresponding MHC class I molecule from column 7 (set 3) in the same row of Table 1A. For example, the method can comprise administering to a TCR or T cell comprising a TCR that can bind to an epitope sequence from column 6 (set 3) of Table 1A in complex with a corresponding MHC class I molecule from column 7 (set 3) in the same row of Table 1A to a subject that expresses the corresponding MHC class I molecule from column 7 (set 3).

[0564] For example, the method can comprise administering to the subject a TCR or T cell comprising a TCR that can bind to an epitope sequence from column 2 (set 1) of Table 1B in complex with a corresponding MHC class I molecule from column 3 (set 1) in the same row of Table 1B. For example, the method can comprise administering to a TCR or T cell comprising a TCR that can bind to an epitope sequence from column 2 (set 1) of Table 1B in complex with a corresponding MHC class I molecule from column 3 (set 1) in the same row of Table 1B to a subject that expresses the corresponding MHC class I molecule from column 3 (set 1). For example, the method can comprise administering to the subject a TCR or T cell comprising a TCR that can bind to an epitope sequence from column 4 (set 2) of Table 1B in complex with a corresponding MHC class I molecule from column 5 (set 2) in the same row of Table 1B. For example, the method can comprise administering to a TCR or T cell comprising a TCR that can bind to an epitope sequence from column 4 (set 2) of Table 1B in complex with a corresponding MHC class I molecule from column 5 (set 2) in the same row of Table 1B to a subject that expresses the corresponding MHC class I molecule from column 5 (set 2).

[0565] For example, the method can comprise administering to the subject a TCR or T cell comprising a TCR that can bind to an epitope sequence from column 2 (set 1) of Table 2Ai in complex with a corresponding MHC class II molecule from column 3 (set 1) in the same row of Table 2Ai. For example, the method can comprise administering to a TCR or T cell comprising a TCR that can bind to an epitope sequence from column 2 (set 1) of Table 2Ai in complex with a corresponding MHC class II molecule from column 3 (set 1) in the same row of Table 2Ai to a subject that expresses the corresponding MHC class II molecule from column 3 (set 1). For example, the method can comprise administering to the subject a TCR or T cell comprising a TCR that can bind to an epitope sequence from column 4 (set 2) of Table 2Ai in complex with a corresponding MHC class II molecule from column 5 (set 2) in the same row of Table 2Ai. For example, the method can comprise administering to a TCR or T cell comprising a TCR that can bind to an epitope sequence from column 4 (set 2) of Table 2Ai in complex with a corresponding MHC class II molecule from column 5 (set 2) in the same row of Table 2Ai to a subject that expresses the corresponding MHC class II molecule from column 5 (set 2). For example, the method can comprise administering to the subject a TCR or T cell comprising a TCR that can bind to an epitope sequence from the left column of Table 2Aii in complex with a corresponding MHC class II molecule from the right column in the same row of Table 2Aii.

[0566] In one embodiment, the antigenic peptide is a viral antigen. In another embodiment, the antigenic peptide is a non-mutated overexpressed antigen. In some embodiments, the viral antigen is derived from publicly disclosed information on the viral genetic information. In some embodiments, the viral antigen is derived from analysis of the viral genome to predict suitable epitopes for T cell activation. In some embodiments, the viral antigen is derived from analysis of the sequence of the viral genome in a MHC-peptide presentation prediction algorithm implemented in a computer processor. In some embodiments, the viral antigen is derived from analysis of the viral sequences in an MHC-peptide presentation prediction algorithm implemented in a computer processor that has been trained by a machine learning software, which predicts the likelihood of binding and presentation of an epitope by an MHC class I or an MHC class II antigen. In some embodiments, the MHC-peptide presentation predictor is neonmhc2.

[0567] In some embodiments, the MHC-peptide presentation prediction algorithm or MHC-peptide presentation predictor is NetMHCpan or NetMHCIIpan and in addition, further analyzed in MHC-peptide presentation predictor NetMHCpan or NetMHCIIpan for comparison. In some embodiments, a skilled artisan may use hidden markov model approach for MHC-peptide presentation prediction. In some embodiments, the peptide prediction model MARIA may be utilized. In some embodiments, the MHC-peptide presentation prediction algorithm or MHC-peptide presentation predictor used is not NetMHCpan or NetMHCIIpan. In some embodiments, the viral sequences are analyzed in MHC-peptide presentation prediction algorithm implemented in a computer processor where the MHC-peptide presentation predictor is neonmhc 1 or neonmhc2, that refer respectively to class I and class II binding prediction. In some embodiments, the MHC-peptide presentation predictor model is RECON, which offers high quality MHC-peptide presentation prediction based on expression, processing and binding capabilities.

[0568] In one aspect, provided herein is a method of treating a viral disease in a subject caused by a coronavirus, comprising: administering to the subject a composition comprising one or more viral peptide antigens, wherein the viral peptide antigens are predicted to bind to an MHC class I or an MHC class II peptide of the subject, and are predicted to be presented by an antigen presenting cell to a T cell of the subject such that an antiviral response is initiated in the subject. In some embodiments, the viral antigen is derived from analysis of the sequence of the viral genome in a MHC-peptide presentation prediction algorithm implemented in a computer processor. In some embodiments, the viral antigen is derived from analysis of the viral sequences in an MHC-peptide presentation prediction algorithm implemented in a computer processor that has been trained by a machine learning software, which predicts the likelihood of binding and presentation of an epitope by an MHC class I or an MHC class II antigen. In some embodiments, the MHC-peptide presentation predictor is neonmhc2. In some embodiments, the method further comprises analyzing nucleic acid sequence derived from viral genome in an MHC-peptide presentation prediction model, comprising an algorithm implemented in a computer processor that has been trained by a machine learning software, wherein the MHC-peptide presentation prediction model predicts the likelihood of binding and presentation of an epitope encoded by the viral genome by an MHC class I or an MHC class II antigen. In some embodiments, the method further comprises analyzing a biological sample from a subject for identification of the MHC class I and MHC class II repertoire, wherein the analyzing comprises analyzing by genome or whole exome sequencing or by analysis of proteins encoded by an HLA gene. In some embodiments, the method further comprises matching the epitopes predicted by the MHC-peptide presentation prediction model that have a high affinity for an MHC class I or an MHC class II peptide encoded by an HLA gene of the subject, and selecting one or more peptides that are predicted to bind an MHC peptide encoded by an HLA gene of the subject with a high affinity ranked by the MHC-peptide presentation prediction model. In some embodiments, the one or more peptides that are selected have been predicted to bind an MHC peptide encoded by an HLA gene of the subject with an affinity of at least 1000 nM. In some embodiments, the one or more peptides that are selected have been predicted to bind an MHC class I peptide encoded by an HLA gene of the subject with an affinity of at least 500 nM. In some embodiments, the one or more peptides that are selected have been predicted to bind an MHC class II peptide encoded by an HLA gene of the subject with an affinity of at least 1000 nM.

[0569] In some embodiments, the MHC-peptide presentation prediction model is programmed to provide a ranking order in decreasing order of a likelihood for a particular epitope or antigenic peptide to bind to an HLA allele that would present the peptide to a T cell receptor. In some embodiments, epitope sequences that have the highest likelihood of binding and being presented by an HLA are selected for preparing a therapeutic. In some embodiments, the selection of the HLA may be restricted by HLA expressed in a subject. In some embodiments, the selection of the HLA may be based on the prevalence (e.g., higher prevalence) of the allele in a population. In some embodiments the epitopes may be selected for preparing a therapeutic based on the higher likelihood for the peptide (epitope) of binding to and being presented by an HLA allele, e.g., an HLA allele of interest. In some embodiments, this % rank value may be determined by evaluating the percentile in which a query peptide scores for a specific allele compared to a fixed set of reference peptides (with a different set of reference peptides for class I and class II). In some embodiments the top 10% of the epitopes that have the highest likelihood of binding to an HLA allele may be selected. In some embodiments the top 2% of the epitopes that have the highest likelihood of binding to an HLA allele may be selected. In some embodiments the top 5% of the epitopes that have the highest likelihood of binding to an HLA allele may be selected. In some embodiments the top 8% of the epitopes that have the highest likelihood of binding to an HLA allele may be selected. In some embodiments the top 1% of the epitopes that have the highest likelihood of binding to an HLA allele may be selected. In some embodiments the top 0.5% of the epitopes that have the highest likelihood of binding to an HLA allele may be selected. In some embodiments the top 0.1% of the epitopes that have the highest likelihood of binding to an HLA allele may be selected. In some embodiments the top 0.01% of the epitopes that have the highest likelihood of binding to an HLA allele may be selected. In some embodiments the selection of the cut off may be dependent on the availability and number of epitopes predicted to have a high likelihood of binding to an HLA allele as determined by the prediction model.

[0570] In some embodiments, the subject may be infected by the virus. In some embodiments, the subject may be at risk of infection by the virus. In some embodiments, the virus is a coronavirus. In some embodiments, the coronavirus is selected from a SARS virus, a MERS coronavirus or a 2019 SARS COV-2 virus. In some embodiments, the one or more viral peptide antigen comprises a peptide comprising at least 8 contiguous amino acids of a sequence in Table 1A, Table 1B, Table 1C, Table 2Ai, Table 2Aii, Table 2B, Table 9, Table 10, Table 11, Table 12, Table 14A, Table 14B, Table 15 or Table 16. In some embodiments, the one or more viral peptide antigen comprises a peptide comprising at least 7 contiguous amino acids of a sequence in Table 1A, Table 1B, Table 1C, Table 2Ai, Table 2Aii, Table 2B, Table 9, Table 10, Table 11, Table 12, Table 14A, Table 14B, Table 15 or Table 16. In some embodiments, the one or more viral peptide antigen comprises a peptide comprising at least 6 contiguous amino acids of a sequence in Table 1A, Table 1B, Table 1C, Table 2Ai, Table 2Aii, Table 2B, Table 9, Table 10, Table 11, Table 12, Table 14A, Table 14B, Table 15 or Table 16.

[0571] In one embodiment, the antigenic peptide is between about 5 to about 50 amino acids in length. In another embodiment, the antigenic peptide is between about 15 to about 35 amino acids in length. In another embodiment, the antigenic peptide is about 15 amino acids or less in length. In another embodiment, the antigenic peptide is between about 8 and about 11 amino acids in length. In another embodiment, the antigenic peptide is 9 or 10 amino acids in length. In one embodiment, the antigenic peptide binds major histocompatibility complex (MHC) class I. In another embodiment, the antigenic peptide binds MHC class I with a binding affinity of less than about 500 nM.

[0572] In one embodiment, the antigenic peptide is about 30 amino acids or less in length. In another embodiment, the antigenic peptide is between about 6 and about 25 amino acids in length. In another embodiment, the antigenic peptide is between about 15 and about 24 amino acids in length. In another embodiment, the antigenic peptide is between about 9 and about 15 amino acids in length. In one embodiment, the antigenic peptide binds MHC class II. In another embodiment, the antigenic peptide binds MHC class II with a binding affinity of less than about 1000 nM.

[0573] In one embodiment, the antigenic peptide further comprises flanking amino acids. In another embodiment, the flanking amino acids are not native flanking amino acids. In one embodiment, the antigenic peptide is linked to at least a second antigenic peptide. In another embodiment, the peptides are linked using a poly-glycine or poly-serine linker. In another embodiment, the second antigenic peptide binds MHC class I or class II with a binding affinity of less than about 1000 nM. In another embodiment, the second antigenic peptide binds MHC class I or class II with a binding affinity of less than about 500 nM. In another embodiment, both of the epitopes bind to human leukocyte antigen (HLA)-A, -B, -C, -DP, -DQ, or -DR. In another embodiment, the antigenic peptide binds a class I HLA and the second antigenic peptide binds a class II HLA. In another embodiment, the antigenic peptide binds a class II HLA and the second antigenic peptide binds a class I HLA.

[0574] In one embodiment, the antigenic peptide further comprises modifications which increase in vivo half-life, cellular targeting, antigen uptake, antigen processing, MHC affinity, MHC stability, or antigen presentation. In another embodiment, the modification is conjugation to a carrier protein, conjugation to a ligand, conjugation to an antibody, PEGylation, polysialylation HESylation, recombinant PEG mimetics, Fc fusion, albumin fusion, nanoparticle attachment, nanoparticulate encapsulation, cholesterol fusion, iron fusion, acylation, amidation, glycosylation, side chain oxidation, phosphorylation, biotinylation, the addition of a surface active material, the addition of amino acid mimetics, or the addition of unnatural amino acids, for example, synthetic amino acids, or f-moc amino acids, D-amino acids N-methyl amino acids. In one embodiment, the cells that are targeted are antigen presenting cells. In another embodiment, the antigen presenting cells are dendritic cells. In another embodiment, the dendritic cells are targeted using DEC205, XCR1, CD197, CD80, CD86, CD123, CD209, CD273, CD283, CD289, CD184, CD85h, CD85j, CD85k, CD85d, CD85g, CD85a, CD141, CD11 c, CD83, TSLP receptor, or CD1a marker. In another embodiment, the dendritic cells are targeted using the CD141, DEC205, or XCR1 marker.

[0575] In one embodiment, provided herein is an in vivo delivery system comprising an antigenic peptide described herein. In another embodiment, the delivery system includes cell-penetrating peptides, nanoparticulate encapsulation, virus like particles, or liposomes. In another embodiment, the cell-penetrating peptide is TAT peptide, herpes simplex virus VP22, transportan, or Antp.

[0576] In one embodiment, provided herein is a cell comprising an antigenic peptide described herein. In another embodiment, the cell is an antigen presenting cell. In another embodiment, the cell is a dendritic cell.

[0577] In one embodiment, provided herein is a composition comprising an antigenic peptide described herein. In another embodiment, the composition comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, or at least 30 of the antigenic peptides comprising an epitope of Table 1A. In another embodiment, the composition comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, or at least 30 of the antigenic peptides comprising an epitope of Table 1B. In another embodiment, the composition comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, or at least 30 of the antigenic peptides comprising an epitope of Table 2B. In another embodiment, the composition comprises between 2 and 20 antigenic peptides. In another embodiment, the composition further comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or at least 25, at least 26, at least 27, at least 28, at least 29, or at least 30 additional antigenic peptides. In another embodiment, the composition comprises between about 4 and about 20 additional antigenic peptides. In another embodiment, the additional antigenic peptide is specific for coronavirus.

[0578] In one embodiment, provided herein is a polynucleotide encoding the antigenic peptide described herein. In another embodiment, the polynucleotide is RNA, optionally a self-amplifying RNA. In some embodiments the polynucleotide is DNA. In another embodiment, the RNA is modified to increase stability, increase cellular targeting, increase translation efficiency, adjuvanticity, cytosol accessibility, and / or decrease cytotoxicity. In another embodiment, the modification is conjugation to a carrier protein, conjugation to a ligand, conjugation to an antibody, codon optimization, increased GC-content, incorporation of modified nucleosides, incorporation of 5′-cap or cap analog, and / or incorporation of a poly-A sequence e.g., an unmasked poly-A sequence, or a disrupted poly-A sequence in which two segments of contiguous A sequences linked by a linker.

[0579] In one embodiment, provided herein is a cell comprising a polynucleotide described herein.

[0580] In one embodiment, provided herein is a vector comprising a polynucleotide described herein. In another embodiment, the polynucleotide is operably linked to a promoter. In another embodiment, the vector is a self-amplifying RNA replicon, plasmid, phage, transposon, cosmid, virus, or virion. In another embodiment, the vector is an adeno-associated virus, herpesvirus, lentivirus, or pseudotypes thereof

[0581] In one embodiment, provided herein is an in vivo delivery system comprising an polynucleotide described herein. In another embodiment, the delivery system includes spherical nucleic acids, viruses, virus-like particles, plasmids, bacterial plasmids, or nanoparticles.

[0582] In one embodiment, provided herein is a cell comprising a vector or delivery system described herein. In another embodiment, the cell is an antigen presenting cell. In another embodiment, the cell is a dendritic cell. In another embodiment, the cell is an immature dendritic cell.

[0583] In some embodiments, provided herein is a composition comprising at least one polynucleotide described herein. In some embodiments, provided herein is a composition comprising one or more antigenic peptides described herein in combination with one or more 2019 SARS CoV-2 vaccines (e.g., mRNA-based vaccines, DNA-based vaccines, AAV-based vaccines, protein-based vaccines). In some embodiments, provided herein is a composition comprising one or more polynucleotides encoding at least one antigenic peptide described herein in combination with one or more 2019 SARS CoV-2 vaccines (e.g., mRNA-based vaccines, DNA-based vaccines, AAV-based vaccines, protein-based vaccines). In some embodiments, provided herein is a single polynucleotide encoding more than one antigenic peptide as described herein. In some embodiments, provided herein is a single polynucleotide encoding (i) at least one antigenic peptide as described herein and (ii) a 2019 SARS CoV-2 protein (e.g., S protein) and / or immunogenic fragments thereof (e.g., receptor binding domain (RBD) of S protein). In another embodiment, the composition comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, or at least 30 of the polynucleotides. In another embodiment, the composition comprises between about 2 and about 20 polynucleotides. In another embodiment, the composition further comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, or at least 30 additional antigenic polynucleotides encoding for additional antigenic peptides. In another embodiment, the composition comprises between about 4 and about 20 additional antigenic polynucleotides. In another embodiment, the polynucleotides and the additional antigenic polynucleotides are linked. In another embodiment, the polynucleotides are linked using nucleic acids that encode a poly-glycine or poly-serine linker.

[0584] In one embodiment, provided herein is a T cell receptor (TCR) capable of binding at least one antigenic peptide described herein. In another embodiment, the TCR is capable of binding the antigenic peptide in the context of MHC class I or class II.

[0585] In one embodiment, provided herein is a chimeric antigen receptor comprising: (i) a T cell activation molecule; (ii) a transmembrane region; and (iii) an antigen recognition moiety capable of binding an antigenic peptide described herein. In another embodiment, CD3-zeta is the T cell activation molecule. In another embodiment, the chimeric antigen receptor further comprises at least one costimulatory signaling domain. In another embodiment, the signaling domain is CD28, 4-1BB, ICOS, OX40, ITAM, or Fc epsilon RI-gamma. In another embodiment, the antigen recognition moiety is capable of binding the antigenic peptide in the context of MHC class I or class II. In another embodiment, the chimeric antigen receptor comprises the CD3-zeta, CD28, CTLA-4, ICOS, BTLA, KIR, LAG3, CD137, OX40, CD27, CD40L, Tim-3, A2aR, or PD-1 transmembrane region.

[0586] In one embodiment, provided herein is a T cell comprising the T cell receptor or chimeric antigen receptor described herein. In one embodiment, the T cell is a helper or cytotoxic T cell.

[0587] In one embodiment, provided herein is a nucleic acid comprising a promoter operably linked to a polynucleotide encoding a T cell receptor described herein. In another embodiment, the TCR is capable of binding the at least one antigenic peptide in the context of major histocompatibility complex (MHC) class I or class II. In one embodiment, the nucleic acid comprises a promoter operably linked to a polynucleotide encoding a chimeric antigen receptor described herein. In another embodiment, the antigen recognition moiety is capable of binding the at least one antigenic peptide in the context of major histocompatibility complex (MHC) class I or class II.

[0588] In one embodiment, provided herein is an antibody capable of binding a peptide comprising an epitope of Table 1A, Table 1B, Table 1C, Table 2Ai, Table 2Aii, Table 2B, Table 9, Table 10, Table 11, Table 12, Table 14A, Table 14B, Table 15 or Table 16. In one embodiment, provided herein is an antibody capable of binding a peptide comprising an epitope of Table 1B. In one embodiment, provided herein is an antibody capable of binding a peptide comprising an epitope of Table 2Ai or Table 2Aii.

[0589] In one embodiment, provided herein is a modified cell transfected or transduced with a nucleic acid described herein. In one embodiment, the modified cell is a T cell, tumor infiltrating lymphocyte, NK-T cell, TCR-expressing cell, CD4+ T cell, CD8+ T cell, or NK cell.

[0590] In one embodiment, provided herein is a composition comprising a T cell receptor or chimeric antigen receptor described herein. In another embodiment, a composition comprises autologous patient T cells containing a T cell receptor or chimeric antigen receptor described herein. In another embodiment, the composition further comprises an immune checkpoint inhibitor. In another embodiment, the composition further comprises at least two immune checkpoint inhibitors. In another embodiment, each of the immune checkpoint inhibitors inhibits a checkpoint protein selected from the group consisting of CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CLIK 1, CHK2, A2aR, and B-7 family ligands or a combination thereof. In another embodiment, each of the immune checkpoint inhibitors interacts with a ligand of a checkpoint protein selected from the group consisting of CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, and B-7 family ligands or a combination thereof.

[0591] In one embodiment, the composition further comprises an immune modulator or adjuvant. In another embodiment, the immune modulator is a co-stimulatory ligand, a TNF ligand, an Ig superfamily ligand, CD28, CD80, CD86, ICOS, CD40L, OX40, CD27, GITR, CD30, DR3, CD69, or 4-1BB. In another embodiment, the immune modulator is at least one an infected cell extract. In another embodiment, the infected cell is autologous to the subject in need of the composition. In another embodiment, the infected cell has undergone lysis or been exposed to UV radiation. In another embodiment, the composition further comprises an adjuvant. In another embodiment, the adjuvant is selected from the group consisting of: Poly(I:C), Poly-ICLC, STING agonist, 1018 ISS, aluminum salts, Amplivax, AS15, BCG, CP-870,893, CpG7909, CyaA, dSLIM, GM-CSF, IC30, IC31, Imiquimod, ImuFact IMP321, IS Patch, ISS, ISCOMATRIX, JuvImmune, LipoVac, MF59, monophosphoryl lipid A, Montanide IMS 1312 VG, Montanide ISA 206 VG, Montanide ISA 50 V2, Montanide ISA 51 VG, OK-432, OM-174, OM-197-MP-EC, ISA-TLR2 agonist, ONTAK, PepTel®. vector system, PLG microparticles, resiquimod, SRL172, virosomes and other virus-like particles, YF-17D, VEGF trap, R848, beta-glucan, Pam3Cys, Pam3CSK4, acrylic or methacrylic polymers, copolymers of maleic anhydride, and QS21 stimulon. In another embodiment, the adjuvant induces a humoral when administered to a subject. In another embodiment, the adjuvant induces a T helper cell type 1 when administered to a subject.

[0592] In one embodiment, provided herein is a method of inhibiting infection by a virus by administering to a subject who has a likelihood of getting infected by the virus, a vaccine composition comprising one or more peptides comprising at least 8 contiguous amino acids from the epitopes defined in Table 1A, Table 1B, Table 1C, Table 2Ai, Table 2Aii or Table 2B, comprising contacting a cell with a peptide, polynucleotide, delivery system, vector, composition, antibody, or cells of the present disclosure.

[0593] In one embodiment, provided herein is a method of treating a viral infection specifically, a coronaviral infection, for example a 2019 SARS CoV-2 infection by enhancing, or prolonging an antiviral response in a subject in need thereof comprising administering to the subject the peptide, polynucleotide, vector, composition, antibody, or cells described herein.

[0594] In one embodiment, the subject is a human. In another embodiment, the subject has a viral infection. In one embodiment, the subject is infected by a respiratory virus, such as an acute respiratory virus, for example, a SARS-like virus or a MERS or MERS-like virus, or more specifically, a coronavirus of the 2019 SARS CoV-2 strain. In some embodiments, the subject is infected with a 2019 SARS CoV-2 coronavirus. In some embodiments, the subject has been detectably infected with the 2019 SARS CoV-2 coronavirus. In some embodiments, the subject is asymptomatic. In some embodiments, the subject is symptomatic. In some embodiments, the subject is not detected to have been infected by a 2019 SARS CoV-2 virus or a related virus, but the subject is in close proximity of an infected person, in an infected area or otherwise at risk of infection.

[0595] In one embodiment of the method, a peptide is administered. In another embodiment, the administration is systemic. In another embodiment of the method, a polynucleotide, optionally RNA, is administered. In one embodiment, the polynucleotide is administered parenterally. In one embodiment, the polynucleotide is administered intravenously. In another embodiment, the polynucleotide is administered intradermally or intramuscularly, or subcutaneously. In one embodiment, the polynucleotide is administered intramuscularly. In one embodiment of the method, a cell is administered. In another embodiment, the cell is a T cell or dendritic cell. In another embodiment, the peptide or polynucleotide comprises an antigen presenting cell targeting moiety.

[0596] In one embodiment, the peptide, polynucleotide, vector, composition, or cells is administered prior to administering concurrent with another therapy, such as another antiviral therapy. In another embodiment, the peptide, polynucleotide, vector, composition, or cells is administered before or after the another antiviral therapy. In another embodiment, administration of the another antiviral therapy is continued throughout antigen peptide, polynucleotide, vector, composition, or cell therapy.

[0597] In one embodiment of the method, an additional agent is administered. In another embodiment, the agent is a chemotherapeutic agent, an immunomodulatory drug, an immune metabolism modifying drug, a targeted therapy, radiation an anti-angiogenesis agent, or an agent that reduces immune-suppression. In another embodiment, the administration of a pharmaceutical composition described herein elicits or promotes a CD4+ T cell immune response. In another embodiment, the administration of a pharmaceutical composition described herein elicits or promotes a CD4+ T cell immune response and a CD8+ T cell immune response.

[0598] In another embodiment, the patient received a chemotherapeutic agent, an immunomodulatory drug, an immune metabolism modifying drug, targeted therapy or radiation prior to and / or during receipt of the antigen peptide or nucleic acid vaccine. In another embodiment, the autologous T cells are obtained from a patient that has already received at least one round of T cell therapy containing an antigen. In another embodiment, the method further comprises adoptive T cell therapy. In another embodiment, the adoptive T cell therapy comprises autologous T cells. In another embodiment, the autologous T cells are targeted against viral antigens. In another embodiment, the adoptive T cell therapy further comprises allogenic T cells. In another embodiment, the allogenic T cells are targeted against viral antigens.

[0599] In one embodiment, provided herein is a method for evaluating the efficacy of treatment comprising: (i) measuring the number or concentration of target cells in a first sample obtained from the subject before administering the modified cell, (ii) measuring the number or concentration of target cells in a second sample obtained from the subject after administration of the modified cell, and (iii) determining an increase or decrease of the number or concentration of target cells in the second sample compared to the number or concentration of target cells in the first sample. In another embodiment, the treatment efficacy is determined by monitoring a clinical outcome; an increase, enhancement or prolongation of antiviral activity by T cells; an increase in the number of antiviral T cells or activated T cells as compared with the number prior to treatment; B cell activity; CD4 T cell activity; or a combination thereof. In another embodiment, the treatment efficacy is determined by monitoring a biomarker. In another embodiment, the treatment effect is predicted by presence of T cells or by presence of a gene signature indicating T cell inflammation or a combination thereof.

[0600] Provided herein a pharmaceutical composition comprising: one or more polypeptides having an amino acid sequence of any one of the sequences depicted in column 2 of Table 11 and 12; or one or more recombinant polynucleotide constructs each encoding a polypeptide having an amino acid sequence of any one of the sequences depicted in column 2 of Table 11 and 12.

[0601] In some embodiments, the one or more polypeptides comprises at least 2, 3, 4, 5, 6, 7 or 8 different polypeptides having an amino acid sequence of any one of the sequences depicted in column 2 of Table 11 and 12; or wherein the one or more recombinant polynucleotide constructs comprises at least 2, 3, 4, 5, 6, 7 or 8 recombinant polynucleotide constructs each encoding a different polypeptide having an amino acid sequence of any one of the sequences depicted in column 2 of Table 11 and 12. In some embodiments, the pharmaceutical composition comprises at least 8 recombinant polynucleotide strings. In some embodiments, the one or more recombinant polynucleotide strings encoding a plurality of coronavirus peptide antigens, comprises a sequence selected from a group of sequences depicted in SEQ ID RS C1n, RS C2n, RS C3n, RSC4n, RS C5n, RS Con, RS C7n, and RS C8n, or a sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to any one of the above. In some embodiments, the recombinant polynucleotide construct comprises an mRNA. In some embodiments, the recombinant polynucleotide construct is an mRNA. In some embodiments, the pharmaceutical composition further comprises one or more lipid components. In some embodiments, the one or more lipids comprise a lipid nanoparticle (LNP). In some embodiments, the LNP encapsulates the recombinant polynucleotide construct. In some embodiments, the pharmaceutical composition is administered to a subject in need thereof.

[0602] Provided herein is a method of treating COVID in a subject in need thereof, comprising administering to the subject a pharmaceutical composition described above. In some embodiments, the pharmaceutical composition is administered in addition to one or more therapeutic for COVID. In some embodiments, the pharmaceutical composition is administered in combination with one or more polypeptides having an amino acid sequence of a 2019 SARS CoV-2 spike protein or fragment thereof; or one or more recombinant polynucleotide constructs encoding a 2019 SARS CoV-2 spike protein or fragment thereof. In some embodiments, the 2019 SARS CoV-2 spike protein or fragment thereof is a SARS-CoV-2 spike protein or a fragment thereof. In some embodiments, the pharmaceutical composition is administered 2-10 weeks after a first administration of the 2019 SARS CoV-2 spike protein or fragment thereof. In some embodiments, the pharmaceutical composition is administered 1-6 months after a first administration of the 2019 SARS CoV-2 spike protein or fragment thereof. In some embodiments, the pharmaceutical composition is administered simultaneously with an administration of the 2019 SARS CoV-2 spike protein or fragment thereof. In some embodiments, the pharmaceutical composition is administered 2-10 weeks before an administration of the 2019 SARS CoV-2 spike protein or fragment thereof. In some embodiments, the pharmaceutical composition is administered 2-10 weeks after the first administration of vaccine comprising a SARS-CoV-2 spike protein or polynucleotide encoding the same. In some embodiments, the pharmaceutical composition is administered 1-6 months after the first administration of a SARS-CoV-2 spike protein or polynucleotide encoding the same. In some embodiments, the pharmaceutical composition is administered simultaneously with the administration of a SARS-CoV-2 spike protein or polynucleotide encoding the same. In some embodiments, the pharmaceutical composition is administered prophylactically. In some embodiments, the pharmaceutical composition is administered once every 1, 2, 3, 4, 5, 6 or more weeks.

[0603] Provided herein is an use of any one of the compositions described herein for preparing a therapeutic for treating or preventing a respiratory viral infection caused by 2019 SARS CoV-2 virus.

[0604] Where aspects or embodiments of the present disclosure are described in terms of a Markush group or other grouping of alternatives, the present disclosure encompasses not only the entire group listed as a whole, but also each member of the group individually and all possible subgroups of the main group, and also the main group absent one or more of the group members. The present disclosure also envisages the explicit exclusion of one or more of any of the group members in the embodiments of the present disclosure.BRIEF DESCRIPTION OF THE DRAWINGS

[0605] FIG. 1A depicts an exemplary flow diagram of a method to identify peptides most relevant to the generation of CD8+ T cell responses against the viral epitopes described herein.

[0606] FIG. 1B shows a graphic representation of the SARS-CoV 2 genome.

[0607] FIG. 2 depicts exemplary graphs of results obtained using a T cell epitope prediction algorithm applied to class I peptide-MHC allele pairs in a validation dataset and comparison of the computed percent-ranks of these pairs with reported MHC-binding assay results. The percent-ranks of peptide-MHC allele pairs which had a binary “Positive” result in the MHC-binding assay were significantly lower than pairs with a “Negative” result. In the more granular positive results, stronger assay results (low<intermediate<high) were associated with significantly lower percent-ranks.

[0608] FIG. 3 depicts experimental validation of HLA-A02:01 predicted epitopes from 2019 SARS COV-2 in human T cell induction assays. 23 peptides that were predicted to be high binders to HLA-A02:01 (see Table 4 of Example 8) were synthesized and assayed in T cell inductions using PBMCs from three human donors. Epitopes were considered to be immunogenic if at least one donor raised a T cell response to the peptide as determined by pMHC multimer technology. Representative flow cytometry plots of pMHC staining using peptides from Table 4 of Example 8 are shown. Multimer positive populations are circled, with the frequency of multimer positive CD8+ T cells shown in the upper right-hand corner of each plot.

[0609] FIG. 4A depicts exemplary graphs of cumulative USA population coverage of HLA alleles for the indicated peptides predicted to be MHC class I epitopes (left) and the cumulative USA population coverage of HLA alleles for 25mer peptides predicted to be MHC class II epitopes (right).

[0610] FIG. 4B depicts a small number of predicted multi-allele binding epitopes from individual 2019 SARS-CoV-2 proteins (alternatively termed 2019-CoV-2 proteins) can achieve broad population coverage. The upper panel shows cumulative HLA-I coverage for USA, EUR, and API populations versus the number of included prioritized HLA-I epitopes for M, N, and S proteins, respectively. Peptide sequences corresponding to the upper panel are shown in Table 6. The lower panel shows cumulative HLA-II coverage for each population versus the number of included prioritized HLA-II 25mers for M, N, and S proteins, respectively. Peptide sequences corresponding to the lower panel are shown in Table 7.

[0611] FIG. 5 depicts results from analysis of publicly available proteomic datasets showing relative 2019 SARS CoV-2 protein expression levels that can be leveraged to prioritize potential vaccine targets. Three datasets examining the proteomic response to 2019 SARS CoV-2 infection (alternatively termed 2019 SARS CoV-2 infection) were re-analyzed and protein abundance was estimated by spectral counts normalized to protein length. Any annotated ORF not shown in the figure was not detected in these proteomic studies. Across all three studies, the nucleocapsid protein is the most abundant protein during 2019 SARS CoV-2 infection.

[0612] FIG. 6A depicts a graphical representation of a string construct described as group 1, also described in Tables 9 and 11.

[0613] FIG. 6B provides a detailed and expanded view of the constructs in FIG. 6A.

[0614] FIG. 7A depicts a graphical representation of a string construct described as group 2, also described in Tables 10 and 12.

[0615] FIG. 7B provides a detailed and expanded view of the constructs in FIG. 7A.

[0616] FIG. 8Ai-8Aii show characterization of BNT mRNA vaccine-induced T cells on a single epitope level. Included data shows epitope responsive T cells for the indicated epitopes in three different participants. The vaccine comprises mRNA encoding a SARS-CoV-2 spike protein of 2019 SARS COV-2 encapsulated in a lipid nanoparticle.

[0617] FIG. 8B shows multimer positive CD8+ cells analysed by flow cytometry for cell surface markers, CCR7, CD45RA, CD3, PD-1, CD38, HLA-DR, CD28 and CD27.

[0618] FIG. 8C shows a mRNA vaccine including the spike proteins S1 and S2, with indicated epitope regions that can bind to specific MHC molecules indicated by the solid shapes along the length, corresponding HLA allele to which it binds is indicated below.

[0619] FIG. 8D shows time course of T cell responses after vaccination of patients with Spike protein mRNA vaccines at different doses (10, 20 and 30 micrograms as indicated). Upper panel shows CD4+ T cell responses, indicated by IFN-g expression using ELISPOT assay. Lower panel shows CD8+ T cell responses, indicated by IFN-g expression using ELISPOT assay. CEF and CEFT are controls CMV, EBV and influenza pools.

[0620] FIG. 8E shows time course of CD4+ T cells and CD8+ T cell responses in older adult population who are administered Spike protein mRNA vaccine (30 microgram each).

[0621] FIG. 9 shows design of vaccine strings comprising ORF-1ab epitopes, with specific use of MS-based HLA-I cleavage predictor information in ordering the epitopes. The design utilizes minimum number of linker sequences.

[0622] FIG. 10A shows experimental design for validating immunogenicity of the string vaccine compositions in an animal model.

[0623] FIG. 10B shows a representative experimental set up of an animal model study to determine the immunogenicity of the four CorVac 2.0 strings when administered in vivo. 5 Groups (16 animals / 8-10 take down at d14 / 8-10 at d28).

[0624] FIG. 11A is a schematic of different dosing schedules for spike vaccine (BNT162b2) and CorVac 2.0.

[0625] FIG. 11B depicts a schematic of an animal study for determining the immune responses elicited by different formulation ratios and doses of CorVac 2.0 strings with BNT162b2 in HLA-A02 transgenic mice.

[0626] FIG. 11C depicts a schematic of an animal study for determining the immune responses elicited by different formulation ratios and doses of CorVac 2.0 strings with BNT16262 in transgenic mice expressing human ACE2.

[0627] FIG. 12A demonstrates sequence variants and mutants across the spike protein in various SARS CoV-2 isolates, and the respective mapping of the vaccine epitope sequences.

[0628] FIG. 12B is a chart showing spike variant frequencies over time.

[0629] FIG. 13A demonstrates sequence variants and mutants across the nucleocapsid protein in various SARS CoV-2 isolates, and the respective mapping of the vaccine epitope sequences.

[0630] FIG. 13B is a chart showing nucleocapsid variant frequencies over time.

[0631] FIG. 14 demonstrates sequence variants and mutants across the membrane protein in various SARS CoV-2 isolates, and the respective mapping of the vaccine epitope sequences.

[0632] FIG. 15 demonstrates sequence variants and mutants across the NSP1 protein in various SARS CoV-2 isolates, and the respective mapping of the vaccine epitope sequences.

[0633] FIG. 16 demonstrates sequence variants and mutants across the NSP2 protein in various SARS CoV-2 isolates, and the respective mapping of the vaccine epitope sequences.

[0634] FIG. 17 demonstrates sequence variants and mutants across the NSP3 protein in various SARS CoV-2 isolates, and the respective mapping of the vaccine epitope sequences.

[0635] FIG. 18 demonstrates sequence variants and mutants across the NSP4 protein in various SARS CoV-2 isolates, and the respective mapping of the vaccine epitope sequences.

[0636] FIG. 19A shows CorVac 2.0-String Design for maximal CD8 and CD4 T cell responses.

[0637] FIG. 19B shows RS-C7 is enriched for known ORF1ab T cell epitopes and avoids most variants of concern / variants of interest (VOC / VOI) mutations.

[0638] FIG. 19C shows RS-C7 is enriched for known nucleocapsid and membrane T cell epitopes and avoids most variants of concern / variants of interest (VOC / VOI) mutations.

[0639] FIG. 20 shows an exemplary experimental set up outlined to test the polynucleotide strings for peptide presentation in complex with the MHC protein.

[0640] FIG. 21 depicts representative data showing an exemplary target epitope presentation verified by mass spectrometry; endogenous, in an experimental set up when the epitope is expressed on A375 cells expressing endogenous HLAs; synthetic, in an experimental set up when the epitope is expressed in cells expressing exogenous HLA.

[0641] FIG. 22 shows a diagrammatic representation of a list of epitopes identified by the above methods using mass spectrometry. The identified epitopes span the viral genome, covering epitopes of the nucleocapsid protein, ORF1ab domains and the membrane protein.

[0642] FIG. 23 shows a representation of a map of all identified CorVac 2.0 epitopes across the viral nucleocapsid, ORF1ab and membrane regions.

[0643] FIG. 24 shows representative data demonstrating Corvac 2.0 strings elicit T cell responses from the nucleocapsid region after one injection at day 0 in BALB / C mice. Immunoreactive T cells are determined by elispot assay (#spots / 1×10{circumflex over ( )}6 cells). Statistical significance determined by two-way ANOVA with Sidak's multiple comparisons tests.

[0644] FIG. 25 shows representative data demonstrating Corvac 2.0 strings elicit T cell responses from the membrane region. after one injection at day 0 in BALB / C mice. Immunoreactive T cells are determined by elispot assay (#spots / 1×10{circumflex over ( )}6 cells). Statistical significance determined by two-way ANOVA with Sidak's multiple comparisons tests.

[0645] FIG. 26 shows a graphical representation of the summary of performances of the different strings tested thus far. Number of stars are proportional to the statistical significance of immunogenicity of each string compared to the vehicle control.

[0646] FIG. 27 shows representative data demonstrating Corvac 2.0 strings elicit T cell responses to epitopes from the nucleocapsid region after one injection at day 0 in HLA-A2tg mice (mice that express humanized HLA-A02:01). T cell immunoreactivity was determined by ELISpot assay (#spots / 1×10{circumflex over ( )}6 cells). Statistical significance was determined by two-way ANOVA with Sidak's multiple comparisons tests. Data is from mice at day 28 after injection of the string composition.

[0647] FIG. 28 shows representative data demonstrating Corvac 2.0 strings elicit T cell responses to epitopes from the membrane region after one injection at day 0 in HLA-A2tg mice (mice that express humanized HLA-A02:01). T cell immunoreactivity was determined by ELISpot assay (#spots / 1×10{circumflex over ( )}6 cells). Statistical significance was determined by two-way ANOVA with Sidak's multiple comparisons tests. Data from mice at day 28 after injection of the string composition.

[0648] FIG. 29 shows representative data demonstrating Corvac 2.0 strings elicit T cell responses to epitopes from the ORF1ab region after one injection at day 0 in HLA-A2tg mice (mice that express humanized HLA-A02:01). T cell immunoreactivity was determined by ELISpot assay (#spots / 1×10{circumflex over ( )}6 cells). Statistical significance was determined by two-way ANOVA with Sidak's multiple comparisons tests. Data is from mice at day 28 after injection of the string composition.

[0649] FIG. 30 is a graphical representation summarizing the statistical significance of immunogenicity of the different strings tested in the HLA-A02 transgenic mouse model compared to vehicle controls and results depicted in FIG. 27, FIG. 28 and FIG. 29. The representation indicates RS-C7 has the most T cell responses across pools in the HLA-A02 transgenic mouse model.

[0650] FIG. 31 shows a graphical representation of the RS-C7 string design showing regions of the string that elicited immune responses as determined by ELISpot assay and epitopes that were confirmed process and presented by HLA using mass spectrometry.

[0651] FIG. 32A shows a graphical representation of the string designs where the encoded nucleocapsid sequence contain, inter alia, tiled overlapping 15-mer epitope sequences with 11 amino acid overlaps.

[0652] FIG. 32B shows a graphical representation of the string designs where the encoded membrane sequence contain, inter alia, tiled 15-mer sequences with 11 amino acid overlaps.

[0653] FIG. 32C shows a graphical representation of the string designs where the encoded ORF 1ab sequence contain, inter alia, tiled 15-mer sequences with 11 amino acid overlaps.

[0654] FIG. 32D shows results from the experimental design shown in FIG. 10B indicating CorVac 2.0 strings do not raise T cell responses from the ORF1ab region in the BALB / C mouse model. In contrast, results shown in FIG. 29, (left, pool 11), (right, pool 12) indicates CorVac 2.0 strings do raise T cell responses from the ORF1ab region in an HLA-A02 transgenic mouse model. Statistical significance determined by one-way ANOVA with Sidak's multiple comparisons tests.

[0655] FIG. 32E is a graphical representation of the summary of performances of the different strings tested in the BALB / C mouse model and demonstrates that RS-C7 has the most T cell responses across pools in the BALB / C mouse model. The RS-C7 string raised the most T cell responses across pools in the BALB / C mouse model.

[0656] FIG. 33 is a graphical representation showing that the CorVac 2.0 String C7 epitopes overlap with few or no regions with mutations of variants of concern.

[0657] FIG. 34A depicts data related to assessment of B cell responses by ELISA for S1 binding antibodies in mouse serum at the indicated timepoints and serum dilutions using the indicated dosing schedules according to FIG. 11A.

[0658] FIG. 34B depicts data related to assessment of B cell responses by ELISA for NP binding antibodies in mouse serum at the indicated timepoints and serum dilutions using the indicated dosing schedules according to FIG. 11A.

[0659] FIG. 35 shows results from ELISA for serum IgG concentrations at day 14, 21 and 35 after treatment (injection) with saline control (NaCl), BNT162b2, the C7 string, or the combinations as indicated using the dosing schedules according to FIG. 11A. Results indicate that inclusion of CorVac 2.0 in a co-formulation setting does not impact Spike-specific Ab development.

[0660] FIG. 36 shows results from a pseudovirus neutralization test (pVNT) using viral particles pseudotyped with VSV envelope containing SARS-CoV-2 spike protein at day 14, 21 and 35 after treatment (injection) with saline control (NaCl), BNT162b2, the C7 string, or the combinations as indicated using the dosing schedules according to FIG. 11A. Results indicate that CorVac 2.0 does not negatively impact formation of neutralizing antibodies against the SARS-CoV-2 viral protein (Wuhan strain).

[0661] FIG. 37A shows lymph node phenotyping results at day 35 using the dosing schedules according to FIG. 11A. B cell populations are indicated by the % of CD19+ cells of the CD45+ cell population. Percentage of activated B cells was determined by the % of IgD-CD3-CD4-CD8-cells; switched B cell percentage is determined by the % of Activated / B220+IgM-CD19+CD138-cells; and % GC B cells was determined by the % of Activated / B220+IgM-CD19+CD138-cells of the total CD45+ cells in the population. Results indicate that inclusion of CorVac 2.0 in a 1:1 coformulation does not affect BNT162b2-driven B cell response, and slightly enhances it.

[0662] FIG. 37B shows lymph node phenotyping results at day 35 using the dosing schedules according to FIG. 11A. Results indicate that inclusion of CorVac 2.0 maintains the frequency of Tfh cells in the lymph node.

[0663] FIG. 38 depicts activation of splenocyte cells that have been stimulated with peptides present in BNT162b2 on day 35 and assessed by flow cytometry for the presence of the activation marker CD69 on bulk T cell population (left panel) or CD4 T cells (middle panel) or CD8 T cells (right panel) using the dosing schedules according to FIG. 11A. Results indicate that activation of T cells when restimulated with spike peptides (spike 1 pool) are increased in vaccine groups that have BNT162b2 (Group 2) and not inhibited in groups that have both CorVac 2.0 and BNT162b2 (Groups 4-7).

[0664] FIG. 39 depicts activation of splenocyte cells that have been stimulated with peptides present in BNT162b2 on day 35 and assessed by flow cytometry for the presence of the activation marker IFN-gamma on bulk T cell population (left panel) or CD8 T cells (middle panel) or CD4 T cells (right panel) using the dosing schedules according to FIG. 11A. Results indicate that activation of T cells when restimulated with spike peptides (spike 1 pool) are increased in vaccine groups that have BNT162b2 (Group 2) and not inhibited in groups that have both CorVac 2.0 and BNT162b2 (Groups 4-7) in the CD3 T cell population and CD8 T cell population, but not significantly increased in any groups in the CD4 T cell population.

[0665] FIG. 40 depicts activation of splenocyte cells that have been stimulated with peptides present in BNT162b2 on day 35 and assessed by flow cytometry for the presence of the activation marker CD69 on bulk T cell population (left panel) or CD4 T cells (middle panel) or CD8 T cells (right panel) using the dosing schedules according to FIG. 11A. Results indicate that activation of T cells when restimulated with spike peptides (spike 2 pool) are increased most dramatically in groups that have been given the BNT162b2 co-formulated in the same LNP (Groups 5-7).

[0666] FIG. 41A depicts activation of splenocyte cells that have been stimulated with peptides present in the nucleocapsid sequence present in the CorVac 2.0 string on day 35 and assessed by flow cytometry for the presence of the activation marker CD69 on bulk T cell population (left panel) or CD4 T cells (middle panel) or CD8 T cells (right panel) using the dosing schedules according to FIG. 11A. Results indicate that activation of T cells when restimulated with nucleocapsid peptides are increased in vaccine groups that have CorVac 2.0 (Group 3) and separately formulated and co-formulated strings of both BNT162b2 and CorVac 2.0 (Group 4 and 5) in the CD3 T cell population and CD8 T cell population, and modestly in the CD4 T cell population.

[0667] FIG. 41B depicts activation of splenocyte cells that have been stimulated with peptides present in the nucleocapsid sequence present in the CorVac 2.0 string on day 35 and assessed by flow cytometry for the presence of the functional marker IFN-gamma on bulk T cell population (left panel) or CD8 T cells (middle panel) or CD4 T cells (right panel) using the dosing schedules according to FIG. 11A. Results indicate that production of INF-gamma in T cells when restimulated with nucleocapsid peptides are increased in vaccine groups that have CorVac 2.0 (Group 3) and co-formulated strings of both BNT162b2 and CorVac 2.0 at the same ratio (Group 5) in the CD3 T cell population and CD4 T cell population, and modestly in the CD8 T cell population.

[0668] FIG. 42 depicts results showing Spike (N and C-terminal) antigen-specific T cell responses by ELISpot assay on samples from day 35 using the dosing schedules according to FIG. 11A. Results indicate that Ag-specific Spike T-cell responses are not inhibited by addition of CorVac 2.0 and are slightly enhanced by the 1:1 co-formulation.

[0669] FIG. 43 depicts results showing nucleocapsid, membrane and Orflab antigen-specific T cell responses by ELISpot assay on samples from day 35 using the dosing schedules according to FIG. 11A. Results indicate that CorVac 2.0 string responses are stronger in the CorVac 2.0 only group but are still present when CorVac 2.0 string is combined with BNT162b2.

[0670] FIG. 44 depicts the effect of BNT162b2 and CorVac 2.0 alone or in combination on the anti-Spike antigen T cell responses by ELISPOT at day 14 and day 35 using the dosing schedules according to FIG. 11A. The kinetic study depicted herein indicates that Spike T cell responses increase after boost in all groups.

[0671] FIG. 45 depicts the effect of booster doses on the CorVac 2.0 immune responses at day 14 and day 35 using the dosing schedules according to FIG. 11A. The kinetic study depicted herein indicates that CorVac 2.0 responses did not increase after boost.

[0672] FIG. 46 depicts polyfunctionality of CD4 and CD8 responses elicited by BNT162b2 and CorVac 2.0 using the dosing schedules according to FIG. 11A after restimulation with cognate peptide groups (Spike N-term, Spike C-term, Nucleocapsid and Membrane, as noted) assayed by flow cytometry. CD4 and CD8 T cell responses were determined to be polyfunctional by the expression of IFNγ+IL-2+TNFα+.

[0673] FIG. 47 shows a graphical representation that summarizes the effects of the different formulations indicated on the left-hand column on spike N-terminal antigen specific responses by CD4 / CD8 cells using the dosing schedules according to FIG. 11A. The number of stars is proportional to the statistical significance and intensity of the response compared to the vehicle control.

[0674] FIG. 48 shows a graphical representation summarizes the effects of the different formulations indicated on the left-hand column on spike C-terminal antigen specific responses by CD4 / CD8 cells using the dosing schedules according to FIG. 11A. The number of stars is proportional to the statistical significance and intensity of the response compared to the vehicle control.

[0675] FIG. 49 shows a graphical representation that summarizes the effects of the different formulations indicated on the left-hand column on nucleocapsid antigen specific responses by CD4 / CD8 cells using the dosing schedules according to FIG. 11A. The number of start is proportional to the statistical significance and intensity of the response compared to the vehicle control.

[0676] FIG. 50 shows a graphical representation that summarizes the effects of the different formulations indicated on the left-hand column on membrane antigen specific responses by CD4 / CD8 cells using the dosing schedules according to FIG. 11A. The number of stars is proportional to the statistical significance and intensity of the response compared to the vehicle control.

[0677] FIG. 51 depicts a schematic of an animal study for determining the immune responses elicited by different formulation ratios and doses of CorVac 2.0 strings with BNT162b2 in transgenic mice expressing human ACE2.

[0678] FIG. 52 shows data from the animal study depicted in FIG. 51, demonstrating that boosting with separately formulated CorVac2.0 at 0.3 μg dose enhances anti-spike IgG production (quantified at day 56). CorVac2.0 alone slightly boosts anti-spike IgG production, separately formulated 3:1 boosts anti-spike IgG production and inclusion of multiple doses of separately formulated CorVac2.0 does not negatively impact anti-spike IgG responses.

[0679] FIG. 53 shows data from the animal study depicted in FIG. 51, demonstrating that boosting with separately formulated CorVac2.0 at 0.3 μg dose enhances anti-spike IgG production (as measured by optical density (OD) at day 56). CorVac2.0 alone slightly boosts anti-spike IgG production, separately formulated 3:1 boosts anti-spike IgG production and inclusion of multiple doses of separately formulated CorVac2.0 does not negatively impact anti-spike IgG responses.

[0680] FIG. 54 shows data from the animal study depicted in FIG. 51, demonstrating anti-spike IgG kinetics over time. A third boost increased anti-spike IgG under all CorVac2.0 variations.

[0681] FIG. 55 shows ELISA data from the animal study depicted in FIG. 51, demonstrating anti-spike IgG levels in serum on the indicated days using the indicated serum dilutions.

[0682] FIG. 56 shows pseudovirus neutralization test (pVNT) data from the animal study depicted in FIG. 51, demonstrating that inclusion of CorVac2.0 does not negatively impact neutralizing titers on the indicated days following treatment with indicated dosing regimens. The pVNT was performed using viral particles pseudotyped with VSV envelope containing SARS-CoV-2 spike protein at the indicated dilutions.

[0683] FIG. 57 shows tetramer staining data using PBLs from the animal study depicted in FIG. 51, showing the percentage of CD8+ T cells specific to the indicated membrane and spike epitopes or epitope combinations indicated, demonstrating that anti-spike responses are not impacted by addition of CorVac2.0.

[0684] FIG. 58 shows tetramer staining data using PBLs from the animal study depicted in FIG. 51, showing the percentage of CD8+ T cells specific to the indicated spike epitopes, demonstrating that anti-spike responses are not impacted by addition of CorVac2.0.

[0685] FIG. 59 shows a spot forming assay from the animal study depicted in FIG. 51, showing the number of spots formed per 1×10{circumflex over ( )}6 cells after treatment with the indicated regimens at day 56, demonstrating that addition of CorVac2.0 in the third booster shot as a separate formulation slightly improves anti-spike T cell responses. CorVac2.0 alone slightly boosts anti-spike T cell responses, separately formulated 3:1 and 9:1 slightly boost anti-spike T cells, and inclusion of multiple doses of separately formulated CorVac2.0 does not negatively impact anti-spike T cell responses.

[0686] FIG. 60 shows a spot forming assay from the animal study depicted in FIG. 51, showing the number of spots formed per 1×10{circumflex over ( )}6 cells after treatment with the indicated regimens at day 56, demonstrating that weak anti-nucleocapsid responses were seen with 1 booster dose, and multiple doses of separately formulated BNT162b2+CorVac2.0 leads to increases in responses. Weak responses to nucleocapsid in K18-hACE2 mice with one CorVac2.0 boost was observed. Increased anti-nucleocapsid responses with increasing number of CorVac2.0 doses was also observed.

[0687] FIG. 61 shows a spot forming assay from the animal study depicted in FIG. 51, showing the number of spots formed per 1×10{circumflex over ( )}6 cells after treatment with the indicated regimens at day 56, demonstrating that the strongest anti-membrane responses were seen in separately formulated groups as a booster; multiple doses of separately formulated BNT162b2+CorVac2.0 lead to increases in responses. Strongest anti-membrane responses were seen in separately formulated conditions. Increased anti-mmbrane responses with increasing number of CorVac2.0 doses was observed.

[0688] FIG. 62 shows data from the animal study depicted in FIG. 51, in which harvested inguinal lymph nodes (a draining lympgh node (dLN)) were dissected and live cell counts were determined after treatment with the indicated regimens. Three samples with 0% viability were removed (G5, G7, G9). The data demonstrate that groups containing a CorVac2.0 boost in combination with BNT162b2 show increased live LN cell counts.

[0689] FIG. 63 shows data from the animal study depicted in FIG. 51, in which harvested lymph nodes were dissected and cell counts of the indicated cell populations as a percentage of CD45.2 cells were determined after treatment with the indicated regimens. The data demonstrate a trend for increased germinal center (GC) cells and CD27+ memory B cells in groups treated with with separately formulated CorVac2.0+BNT162.

[0690] FIG. 64A shows data from the animal study depicted in FIG. 51, in which harvested lymph nodes were dissected and cell counts of the indicated cell populations as a percentage of CD45.2 cells were determined after treatment with the indicated regimens. The data demonstrate slightly higher class-switched B cells in groups treated with with separately formulated CorVac2.0+BNT162.

[0691] FIG. 64B shows data from the animal study depicted in FIG. 51, in which harvested lymph nodes were dissected and toal cell counts of the indicated cell populations were determined after treatment with the indicated regimens. The data demonstrate slightly higher class-switched B cells in groups treated with with separately formulated CorVac2.0+BNT162

[0692] FIG. 65 shows tetramer-specific staing data from the animal study depicted in FIG. 51, from harvested lymph node samples showing the percentage of CD8+ T cells specific to spike or membrane epitopes. Also depicted is a graph showing the percentage of central memory T cells, effector memory T cells, naive T cells and effector T cells cells as a percentage of spike positive CD8 T cells. Slightly less differentiated cells in CorVac2.0 treated groups were observed.

[0693] FIG. 66 depicts a schematic of an animal study for determining the immune responses elicited by different formulation ratios and doses of CorVac 2.0 strings with BNT162b2 in HLA-A02 transgenic mice.

[0694] FIG. 67A shows a spot forming assay from the animal study depicted in FIG. 66, showing the number of spots formed per 1×10{circumflex over ( )}6 cells after treatment with the indicated regimens at day 14, demonstrating that CorVac2.0 induces the strongest immune responses at the highest dose.

[0695] FIG. 67B shows a spot forming assay from the animal study depicted in FIG. 66, showing the number of spots formed per 1×10{circumflex over ( )}6 cells after treatment with the indicated regimens at day 35, demonstrating that Spike T cell responses are enhanced with CorVac2.0 inclusion. The dose of 1 μg yielded the strongest responses.

[0696] FIG. 67C shows a spot forming assay from the animal study depicted in FIG. 66, showing the number of spots formed per 1×10{circumflex over ( )}6 cells over time. Improved T cell responses to all regions were observed after the boost.

[0697] FIG. 67D shows a co-culture spot forming assay from the animal study depicted in FIG. 66, showing the number of spots formed per 1×10{circumflex over ( )}6 cells after treatment with the indicated regimens at day 35. Spike responses were seen in CD4 and CD8 T cells. Spike CD8 T cells show more cytokine secretion and degranulation than CD4 T cells.

[0698] FIG. 67E shows a co-culture spot forming assay from the animal study depicted in FIG. 66, showing the number of spots formed per 1×10{circumflex over ( )}6 cells after treatment with the indicated regimens at day 35. Membrane responses were seen in CD4 and CD8 T cells and were strongest at the highest dose. IL2 secretion was seen in CD4 and CD8 T cells.

[0699] FIG. 67F shows a spot forming assay from the animal study depicted in FIG. 66, showing the number of spots formed per 1×10{circumflex over ( )}6 cells after treatment with the indicated regimens at day 56. Spike responses were not negatively impacted by CorVac2.0. CorVac2.0 alone boosted spike responses. Boost with CorVac2.0 alone increased spike responses. No statistically significant changes in spike responses were seen with inclusion of CorVac2.0. The strongest membrane responses were observed in the highest dose groups. The strongest N responseswere observed in CorVac2.0 alone at the highest dose. The strongest Orf1ab responses were observed in CorVac2.0 alone and the separately formulated 3:1 dose.

[0700] FIG. 67G shows a co-culture spot forming assay from the animal study depicted in FIG. 66, showing the number of spots formed per 1×10{circumflex over ( )}6 cells after treatment with the indicated regimens at day 56. Spike responses were seen in CD4 and CD8 T cells and some were boosted by inclusion of CorVac2.0.

[0701] FIG. 67H shows a co-culture spot forming assay from the animal study depicted in FIG. 66, showing the number of spots formed per 1×10{circumflex over ( )}6 cells after treatment with the indicated regimens at day 56. Polyfunctional spike CD4 and CD8 T cells were slightly enhanced in higher dose CorVac2.0 conditions.

[0702] FIG. 67I shows a co-culture spot forming assay from the animal study depicted in FIG. 66, showing the number of spots formed per 1×10{circumflex over ( )}6 cells after treatment with the indicated regimens at day 56. Membrane responses seen more strongly in CD8 T cells.

[0703] FIG. 67J shows a co-culture spot forming assay from the animal study depicted in FIG. 66, showing the number of spots formed per 1×10{circumflex over ( )}6 cells after treatment with the indicated regimens at day 56. Polyfunctional membrane CD4 and CD8 T cells were observed.

[0704] FIG. 68A shows phenotyping data from the animal study depicted in FIG. 66, in which harvested lymph nodes were dissected and cell counts of the indicated cell populations as a percentage of CD45.2 cells were determined after treatment with the indicated regimens at day 14. Memory B cells: CD3-IgD-IgM-CD27+; Activated B cells: IgD-CD3-CD4-CD8-; Switched B cells: IgD-CD3-CD4-CD8-B220+IgM-CD19+CD138-. GC B cells: IgD-CD3-CD4-CD8-B220+IgM-CD19+CD138-CD95+CD38-.

[0705] FIG. 68B shows phenotyping data from the animal study depicted in FIG. 66, in which harvested lymph nodes were dissected and cell counts of the indicated cell populations as a percentage of CD45.2 cells were determined after treatment with the indicated regimens at day 35. Memory B cells: CD3-IgD-IgM-CD27+; Activated B cells: IgD-CD3-CD4-CD8-; Switched B cells: IgD-CD3-CD4-CD8-B220+IgM-CD19+CD138-. GC B cells: IgD-CD3-CD4-CD8-B220+IgM-CD19+CD138-CD95+CD38-. The addition of CorVac2.0 to BNT162b2 slightly enhances class-switching and GC B cells. CorVac2.0 leads to a slight increase in Tfh cells.

[0706] FIG. 68C shows phenotyping data from the animal study depicted in FIG. 66, in which harvested lymph nodes were dissected and cell counts of the indicated cell populations as a percentage of CD45.2 cells were determined after treatment with the indicated regimens at day 56. Memory B cells: CD3-IgD-IgM-CD27+; Activated B cells: IgD-CD3-CD4-CD8-; Switched B cells: IgD-CD3-CD4-CD8-B220+IgM-CD19+CD138-. GC B cells: IgD-CD3-CD4-CD8-B220+IgM-CD19+CD138-CD95+CD38-. Boosting with CorVac2.0 alone enhances B cell responses compared to no boost. CorVac2.0 does not significantly affect B cells responses in combination with BNT162b2.

[0707] FIG. 69 shows an exemplary clinical study design to evaluate safety of CorVac 2.0 vaccines in healthy human subjects.

[0708] FIG. 70 shows an exemplary clinical study design to evaluate safety of CorVac 2.0 vaccines in immunocompromised human subjects.

[0709] FIG. 71 shows an exemplary clinical study design to evaluate safety of CorVac 2.0 vaccines in immunocompromised human subjects.

[0710] FIG. 72 demonstrates sequence variants and mutants across the Spike protein in various SARS CoV-2 isolates as indicated on the right hand side. The data shows that the Spike protein is highly mutated putitively due to selective pressure.

[0711] FIG. 73 demonstrates sequence variants and mutants across the nucleocapsid (N) and membrane (M) protein in various SARS CoV-2 isolates as indicated on the right hand side, and the respective mapping of the vaccine epitope sequences in encoded by CorVac 2.0. The data shows that the CorVac2.0 vaccine sequence is rarely impacted by variant mutations in N, M.

[0712] FIG. 74 demonstrates sequence variants and mutants across the ORF 1ab in various SARS COV-2 isolates as indicated on the right hand side, and the respective mapping of the vaccine epitope sequences in encoded by CorVac 2.0. The data shows that the CorVac2.0 vaccine sequence is rarely impacted by variant mutations in ORF1ab.

[0713] FIG. 75A shows a representation of a map of an exemplary CorVac2.0 RS-C7 string depicting linkers, the SEC domain, the transmembrane (TM) domain and the viral epitopes contained within the string, including nucleocapsid epitopes, ORF1ab epitopes, and membrane epitopes.

[0714] FIG. 75B shows a representation of a map of an exemplary CorVac2.0 RS-C7 string depicting the viral epitopes contained within the string that were observed as being presented by mass spectrometry (MS), including nucleocapsid epitopes, ORF1ab epitopes, and membrane epitopes.

[0715] FIG. 76 shows a representation of an MS-based HLA-I cleavage predictor used to optimize ordering of candidate ORF1ab sequences, adding as few linkers as possible while retaining efficient epitope cleavage (top) and 18 ORF1ab epitopes optimized for GSS linker contexts.

[0716] FIG. 77A-C shows a representation of a map of an exemplary CorVac2.0 RS-C7 string Antigens chosen for CorVac 2.0 are rarely mutated: across all WHO-designated variants, RS-C7 is only impacted by 3 mutations, leaving the vast majority of epitopes unchanged. As shown in FIG. 77B-C, even in the highly mutated Omicron variants, only one mutation impacts CorVac 2.0 strings (in contrast to ~39 amino acid changes in Spike protein).

[0717] FIG. 78A-78B shows kinetics of the antibody concentration against the Spike protein.

[0718] FIG. 79 depicts an exemplary structure of RS C7, and illustrates certain factors that were considered when designing a CorVac 2.0 string. “Count”, as used in FIG. 79, refers to the number of pMHC-allele pairs that overlap with an indicated residue of a protein sequence. Counts can be determined by reference to a database of epitopes (e.g., a database of epitopes that have been observed, for example, in experimental studies, and / or predicted). “Entropy” as used in FIG. 79 refers to Shannon entropy, and is a measure of conservation level (where lower entropy indicates higher conservation).

[0719] FIG. 80A depicts epitopes present in an exemplary CorVac 2.0 string (e.g., RS C7 string) that were observed via mass spectrometery as processed and presented by MHC complexes.

[0720] FIG. 80B depicts data for one exemplary epitope observed by mass spectrometry (epitope 23 of Table 19).

[0721] FIG. 81 depicts a study design to test the immunogenicity of various BNT162b2+CorVac2.0 string dosing regimens in K18-hACE2 mice.

[0722] FIG. 82A-82B show anti-Spike protein, IgG concentrations measured over time, from serum samples collected from the experiment depicted in FIG. 81. IgG concentrations measured by ELISA. Error bars indicate standard error of the mean.

[0723] FIG. 83A-83B show neutralization titers measured from the serum samples collected from the experiment depicted in FIG. 81. Neutralization titers were measured using a pseudovirus neutralization assay, using pseudoviruses comprising an SARS-CoV-2 S protein from a Wuhan stain.

[0724] FIG. 84 depicts an experimental protocol for measuring the efficacy of a CorVac2.0 string, administered alone or in combination with RNA encoding a SARS-CoV-2 S protein in Syrian Hamsters.

[0725] FIG. 85 shows results from the study depicted in FIG. 84. Specifically, FIG. 85 shows changes in body weight of hamsters, following challenge with SARS-CoV-2 (Wuhan strain).

[0726] FIG. 86 shows an exemplary protocol for clonotype analysis of Spike-specific B cells and T cells.

[0727] FIG. 87 summarizes T cell clonotypes observed in animals administered (i) two doses of RNA encoding a SARS-CoV-2 S protein (BNT162b2) or (ii) two doses of RNA encoding a SARS-CoV-2 S protein and one dose of CorVac2.0 (String C7). Circles correspond to samples having the same clonotype, with clonotypes in the same “clonotype cluster” (i.e., clonotypes having similar sequences) indicated with lines connecting dots. As shown in the figure, administration of a CorVac2.0 construct increases the trend towards higher clonal expansion, but does not negatively impact clonality.

[0728] FIG. 88 shows an exemplary clinical study design to evaluate safety of CorVac 2.0 vaccines in healthy human subjects. “Spike Vac” refers to RNA encoding a SARS-CoV-2 S protein and comprising one or more mutations that stabilize the prefusion conformation (e.g., one or more mutations disclosed herein or known in the art); in the exemplary clinical study design, a bivalent vaccine is administered, comprising RNA encoding a SARS-CoV-2 S polypeptide of a Wuhan strain and a SARS-CoV-2 S polypeptide comprising one or more mutations characteristic of a BA.4 / 5 Omicron variant (e.g., one or more mutations disclosed herein). aFurther dosing of subjects or opening of new cohorts may proceed if acceptable tolerability is shown and no stopping / pausing rules are met. bAn exemplary Spike Vac Bivalent is BNT162b2 Bivalent (Wuhan+OMI BA.4 / BA.5). Abbreviations: d=days; h=hour(s); FIH=first-in-human; IRC=Internal Review Committee; N=number of subjects; OMI=Omicron; WT=Wild Type. Trial population: Healthy volunteers aged 18-55 years, who have been previously vaccinated with at least three doses of any authorized COVID19 RNA vaccine (the last COVID19 RNA vaccine dose must have been administered at least 4 months before Visit 1). Subjects who have had SARS-CoV-2 infection 60 d or more prior to randomization are not excluded from the trial.DETAILED DESCRIPTION

[0729] Described herein are novel therapeutics and vaccines based on viral epitopes. Accordingly, the present disclosure described herein provides peptides, polynucleotides encoding the peptides, and peptide binding agents that can be used, for example, to stimulate an immune response to a viral antigen, to create an immunogenic composition or vaccine for use in treating or preventing a viral infection.Definitions

[0730] To facilitate an understanding of the present disclosure, a number of terms and phrases are defined below.

[0731] “Viral antigens” refer to antigens encoded by a virus. They include, but are not limited to, antigens of coronaviruses, such as COVID19.

[0732] Throughout this disclosure, “binding data” results can be expressed in terms of “IC50.” IC50 is the concentration of the tested peptide in a binding assay at which 50% inhibition of binding of a labeled reference peptide is observed. Given the conditions in which the assays are run (i.e., limiting HLA protein and labeled reference peptide concentrations), these values approximate KD values. Assays for determining binding are well known in the art and are described in detail, for example, in PCT publications WO 94 / 20127 and WO 94 / 03205, and other publications such Sidney et al., Current Protocols in Immunology 18.3.1 (1998); Sidney, et al., J. Immunol. 154:247 (1995); and Sette, et al., Mol. Immunol. 31:813 (1994). Alternatively, binding can be expressed relative to binding by a reference standard peptide. For example, can be based on its IC50, relative to the IC50 of a reference standard peptide. Binding can also be determined using other assay systems including those using: live cells (e.g., Ceppellini et al., Nature 339:392 (1989); Christnick et al., Nature 352:67 (1991); Busch et al., Int. Immunol. 2:443 (1990); Hill et al., J. Immunol. 147:189 (1991); del Guercio et al., J. Immunol. 154:685 (1995)), cell free systems using detergent lysates (e.g., Cerundolo et al., J. Immunol 21:2069 (1991)), immobilized purified MHC (e.g., Hill et al., J. Immunol. 152, 2890 (1994); Marshall et al., J. Immunol. 152:4946 (1994)), ELISA systems (e.g., Reay et al., EMBO J. 11:2829 (1992)), surface plasmon resonance (e.g., Khilko et al., J. Biol. Chem. 268:15425 (1993)); high flux soluble phase assays (Hammer et al., J. Exp. Med. 180:2353 (1994)), and measurement of class I MHC stabilization or assembly (e.g., Ljunggren et al., Nature 346:476 (1990); Schumacher et al., Cell 62:563 (1990); Townsend et al., Cell 62:285 (1990); Parker et al., J. Immunol. 149:1896 (1992)).

[0733] The term “derived” when used to discuss an epitope is a synonym for “prepared.” A derived epitope can be from a natural source, or it can be synthesized according to standard protocols in the art. Synthetic epitopes can comprise artificial amino acid residues “amino acid mimetics,” such as D isomers of natural occurring L amino acid residues or non-natural amino acid residues such as cyclohexylalanine. A derived or prepared epitope can be an analog of a native epitope.

[0734] A “diluent” includes sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is also a diluent for pharmaceutical compositions. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as diluents, for example, in injectable solutions.

[0735] An “epitope” is the collective features of a molecule, such as primary, secondary and tertiary peptide structure, and charge, that together form a site recognized by, for example, an immunoglobulin, T cell receptor, HLA molecule, or chimeric antigen receptor. Alternatively, an epitope can be a set of amino acid residues which is involved in recognition by a particular immunoglobulin, or in the context of T cells, those residues necessary for recognition by T cell receptor proteins, chimeric antigen receptors, and / or Major Histocompatibility Complex (MHC) receptors. Epitopes can be prepared by isolation from a natural source, or they can be synthesized according to standard protocols in the art. Synthetic epitopes can comprise artificial amino acid residues, “amino acid mimetics,” such as D isomers of naturally-occurring L amino acid residues or non-naturally-occurring amino acid residues such as cyclohexylalanine. Throughout this disclosure, epitopes may be referred to in some cases as peptides or peptide epitopes.

[0736] It is to be appreciated that proteins or peptides that comprise an epitope or an analog described herein as well as additional amino acid(s) are still within the bounds of the present disclosure. In certain embodiments, the peptide comprises a fragment of an antigen.

[0737] In certain embodiments, there is a limitation on the length of a peptide of the present disclosure. The embodiment that is length-limited occurs when the protein or peptide comprising an epitope described herein comprises a region (i.e., a contiguous series of amino acid residues) having 100% identity with a native sequence. In order to avoid the definition of epitope from reading, e.g., on whole natural molecules, there is a limitation on the length of any region that has 100% identity with a native peptide sequence. Thus, for a peptide comprising an epitope described herein and a region with 100% identity with a native peptide sequence, the region with 100% identity to a native sequence generally has a length of: less than or equal to 600 amino acid residues, less than or equal to 500 amino acid residues, less than or equal to 400 amino acid residues, less than or equal to 250 amino acid residues, less than or equal to 100 amino acid residues, less than or equal to 85 amino acid residues, less than or equal to 75 amino acid residues, less than or equal to 65 amino acid residues, and less than or equal to 50 amino acid residues. In certain embodiments, an “epitope” described herein is comprised by a peptide having a region with less than 51 amino acid residues that has 100% identity to a native peptide sequence, in any increment down to 5 amino acid residues; for example 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5 amino acid residues.

[0738] “Human Leukocyte Antigen” or “HLA” is a human class I or class II Major Histocompatibility Complex (MITC) protein (see, e.g., Stites, et al., IMMUNOLOGY, 8TH ED., Lange Publishing, Los Altos, Calif. (1994).

[0739] An “HLA supertype or HLA family”, as used herein, describes sets of HLA molecules grouped on the basis of shared peptide-binding specificities. HLA class I molecules that share somewhat similar binding affinity for peptides bearing certain amino acid motifs are grouped into such HLA supertypes. The terms HLA superfamily, HLA supertype family, HLA family, and HLA xx-like molecules (where “xx” denotes a particular HLA type), are synonyms.

[0740] The terms “identical” or percent “identity,” in the context of two or more peptide sequences or antigen fragments, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues that are the same, when compared and aligned for maximum correspondence over a comparison window, as measured using a sequence comparison algorithm or by manual alignment and visual inspection.

[0741] An “immunogenic” peptide or an “immunogenic” epitope or “peptide epitope” is a peptide that comprises an allele-specific motif such that the peptide will bind an HLA molecule and induce a cell-mediated or humoral response, for example, cytotoxic T lymphocyte (CTL), helper T lymphocyte (HTL) and / or B lymphocyte response. Thus, immunogenic peptides described herein are capable of binding to an appropriate HLA molecule and thereafter inducing a CTL (cytotoxic) response, or a HTL (and humoral) response, to the peptide.

[0742] As used herein, a “chimeric antigen receptor” or “CAR” refers to an antigen binding protein in that includes an immunoglobulin antigen binding domain (e.g., an immunoglobulin variable domain) and a T cell receptor (TCR) constant domain. As used herein, a “constant domain” of a TCR polypeptide includes a membrane-proximal TCR constant domain, and may also include a TCR transmembrane domain and / or a TCR cytoplasmic tail. For example, in some embodiments, the CAR is a dimer that includes a first polypeptide comprising a immunoglobulin heavy chain variable domain linked to a TCR-beta constant domain and a second polypeptide comprising an immunoglobulin light chain variable domain (e.g., a lc or 2\., variable domain) linked to a TCRα constant domain. In some embodiments, the CAR is a dimer that includes a first polypeptide comprising a immunoglobulin heavy chain variable domain linked to a TCRα constant domain and a second polypeptide comprising an immunoglobulin light chain variable domain linked to a TCRβ constant domain.

[0743] The phrases “isolated” or “biologically pure” refer to material which is substantially or essentially free from components which normally accompany the material as it is found in its native state. Thus, peptides described herein do not contain some or all of the materials normally associated with the peptides in their in situ environment. An “isolated” epitope refers to an epitope that does not include the whole sequence of the antigen from which the epitope was derived. Typically, the “isolated” epitope does not have attached thereto additional amino acid residues that result in a sequence that has 100% identity over the entire length of a native sequence. The native sequence can be a sequence such as a viral antigen from which the epitope is derived. Thus, the term “isolated” means that the material is removed from its original environment (e.g., the natural environment if it is naturally occurring). For example, a naturally-occurring polynucleotide or peptide present in a living animal is not isolated, but the same polynucleotide or peptide, separated from some or all of the coexisting materials in the natural system, is isolated. Such a polynucleotide could be part of a vector, and / or such a polynucleotide or peptide could be part of a composition, and still be “isolated” in that such vector or composition is not part of its natural environment. RNA molecules include in vivo or in vitro RNA transcripts of the DNA molecules described herein, and further include such molecules produced synthetically.

[0744] “Major Histocompatibility Complex” or “MHC” is a cluster of genes that plays a role in control of the cellular interactions responsible for physiologic immune responses. In humans, the MHC complex is also known as the human leukocyte antigen (HLA) complex. For a detailed description of the MHC and HLA complexes, see, Paul, FUNDAMENTAL IMMUNOLOGY, 3.sup.RD ED., Raven Press, New York (1993).

[0745] A “native” or a “wild type” sequence refers to a sequence found in nature. Such a sequence can comprise a longer sequence in nature.

[0746] A “T cell epitope” is to be understood as meaning a peptide sequence which can be bound by the MHC molecules of class I or II in the form of a peptide-presenting MHC molecule or MHC complex and then, in this form, be recognized and bound by cytotoxic T-lymphocytes or T-helper cells, respectively.

[0747] A “receptor” is to be understood as meaning a biological molecule or a molecule grouping capable of binding a ligand. A receptor may serve, to transmit information in a cell, a cell formation or an organism. The receptor comprises at least one receptor unit, for example, where each receptor unit may consist of a protein molecule. The receptor has a structure which complements that of a ligand and may complex the ligand as a binding partner. The information is transmitted in particular by conformational changes of the receptor following complexation of the ligand on the surface of a cell. In some embodiments, a receptor is to be understood as meaning in particular proteins of MHC classes I and II capable of forming a receptor / ligand complex with a ligand, in particular a peptide or peptide fragment of suitable length.

[0748] A “ligand” is to be understood as meaning a molecule which has a structure complementary to that of a receptor and is capable of forming a complex with this receptor. In some embodiments, a ligand is to be understood as meaning a peptide or peptide fragment which has a suitable length and suitable binding motifs in its amino acid sequence, so that the peptide or peptide fragment is capable of forming a complex with proteins of MHC class I or MHC class II.

[0749] In some embodiments, a “receptor / ligand complex” is also to be understood as meaning a “receptor / peptide complex” or “receptor / peptide fragment complex”, including a peptide- or peptide fragment-presenting MHC molecule of class I or of class II.

[0750] “Proteins or molecules of the major histocompatibility complex (MHC)”, “MHC molecules”, “MHC proteins” or “HLA proteins” are to be understood as meaning proteins capable of binding peptides resulting from the proteolytic cleavage of protein antigens and representing potential lymphocyte epitopes, (e.g., T cell epitope and B cell epitope) transporting them to the cell surface and presenting them there to specific cells, in particular cytotoxic T-lymphocytes, T-helper cells, or B cells. The major histocompatibility complex in the genome comprises the genetic region whose gene products expressed on the cell surface are important for binding and presenting endogenous and / or foreign antigens and thus for regulating immunological processes. The major histocompatibility complex is classified into two gene groups coding for different proteins, namely molecules of MHC class I and molecules of MHC class II. The cellular biology and the expression patterns of the two MHC classes are adapted to these different roles.

[0751] The terms “peptide” and “peptide epitope” are used interchangeably with “oligopeptide” in the present specification to designate a series of residues connected one to the other, typically by peptide bonds between the α-amino and carboxyl groups of adjacent amino acid residues.

[0752] “Synthetic peptide” refers to a peptide that is obtained from a non-natural source, e.g., is man-made. Such peptides can be produced using such methods as chemical synthesis or recombinant DNA technology. “Synthetic peptides” include “fusion proteins.”

[0753] A “PanDR binding” peptide, a “PanDR binding epitope” is a member of a family of molecules that binds more than one HLA class II DR molecule.

[0754] “Pharmaceutically acceptable” refers to a generally non-toxic, inert, and / or physiologically compatible composition or component of a composition.

[0755] A “pharmaceutical excipient” or “excipient” comprises a material such as an adjuvant, a carrier, pH-adjusting and buffering agents, tonicity adjusting agents, wetting agents, preservatives, and the like. A “pharmaceutical excipient” is an excipient which is pharmaceutically acceptable. The term “motif refers to a pattern of residues in an amino acid sequence of defined length, for example, a peptide of less than about 15 amino acid residues in length, or less than about 13 amino acid residues in length, for example, from about 8 to about 13 amino acid residues (e.g., 8, 9, 10, 11, 12, or 13) for a class I HLA motif and from about 6 to about 25 amino acid residues (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25) fora class II HLA motif, which is recognized by a particular HLA molecule. Motifs are typically different for each HLA protein encoded by a given human HLA allele. These motifs differ in their pattern of the primary and secondary anchor residues. In some embodiments, an MHC class I motif identifies a peptide of 9, 10, or 11 amino acid residues in length.

[0756] A “supermotif’ is a peptide binding specificity shared by HLA molecules encoded by two or more HLA alleles. In some embodiments, a supermotif-bearing peptide described herein is recognized with high or intermediate affinity (as defined herein) by two or more HLA antigens.

[0757] The term “naturally occurring” as used herein refers to the fact that an object can be found in nature. For example, a peptide or nucleic acid that is present in an organism (including viruses) and can be from a source in nature and which has not been intentionally modified by man in the laboratory is naturally occurring.

[0758] According to the present disclosure, the term “vaccine” relates to a pharmaceutical preparation (pharmaceutical composition) or product that upon administration induces an immune response, for example, a cellular or humoral immune response, which recognizes and attacks a pathogen or a diseased cell such as a cell infected with a virus. A vaccine may be used for the prevention or treatment of a disease.

[0759] A “protective immune response” or “therapeutic immune response” refers to a CTL and / or an HTL response to an antigen derived from an pathogenic antigen (e.g., a viral antigen), which in some way prevents or at least partially arrests disease symptoms, side effects or progression. The immune response can also include an antibody response which has been facilitated by the stimulation of helper T cells.

[0760] “Antigen processing” or “processing” refers to the degradation of a polypeptide or antigen into procession products, which are fragments of said polypeptide or antigen (e.g., the degradation of a polypeptide into peptides) and the association of one or more of these fragments (e.g., via binding) with MHC molecules for presentation by cells, for example, antigen presenting cells, to specific T cells.

[0761] “Antigen presenting cells” (APC) are cells which present peptide fragments of protein antigens in association with MHC molecules on their cell surface. Some APCs may activate antigen specific T cells. Professional antigen-presenting cells are very efficient at internalizing antigen, either by phagocytosis or by receptor-mediated endocytosis, and then displaying a fragment of the antigen, bound to a class II MHC molecule, on their membrane. The T cell recognizes and interacts with the antigen-class II MHC molecule complex on the membrane of the antigen presenting cell. An additional co-stimulatory signal is then produced by the antigen presenting cell, leading to activation of the T cell. The expression of co-stimulatory molecules is a defining feature of professional antigen-presenting cells.

[0762] The main types of professional antigen-presenting cells are dendritic cells, which have the broadest range of antigen presentation, and are probably the most important antigen presenting cells, macrophages, B-cells, and certain activated epithelial cells.

[0763] Dendritic cells (DCs) are leukocyte populations that present antigens captured in peripheral tissues to T cells via both MHC class II and I antigen presentation pathways. It is well known that dendritic cells are potent inducers of immune responses and the activation of these cells is a critical step for the induction of antiviral immunity.

[0764] Dendritic cells are conveniently categorized as “immature” and “mature” cells, which can be used as a simple way to discriminate between two well characterized phenotypes. However, this nomenclature should not be construed to exclude all possible intermediate stages of differentiation.

[0765] Immature dendritic cells are characterized as antigen presenting cells with a high capacity for antigen uptake and processing, which correlates with the high expression of Fey receptor and mannose receptor. The mature phenotype is typically characterized by a lower expression of these markers, but a high expression of cell surface molecules responsible for T cell activation such as class I and class II MHC, adhesion molecules (e. g. CD54 and CD11) and costimulatory molecules (e. g., CD40, CD80, CD86 and 4-1 BB).

[0766] The term “residue” refers to an amino acid residue or amino acid mimetic residue incorporated into a peptide or protein by an amide bond or amide bond mimetic, or nucleic acid (DNA or RNA) that encodes the amino acid or amino acid mimetic.

[0767] The nomenclature used to describe peptides or proteins follows the conventional practice wherein the amino group is presented to the left (the amino- or N-terminus) and the carboxyl group to the right (the carboxy- or C-terminus) of each amino acid residue. When amino acid residue positions are referred to in a peptide epitope they are numbered in an amino to carboxyl direction with position one being the residue located at the amino terminal end of the epitope, or the peptide or protein of which it can be a part.

[0768] In the formulae representing selected specific embodiments of the present disclosure, the amino- and carboxyl-terminal groups, although not specifically shown, are in the form they would assume at physiologic pH values, unless otherwise specified. In the amino acid structure formulae, each residue is generally represented by standard three letter or single letter designations. The L-form of an amino acid residue is represented by a capital single letter or a capital first letter of a three-letter symbol, and the D-form for those amino acid residues having D-forms is represented by a lower case single letter or a lower case three letter symbol. However, when three letter symbols or full names are used without capitals, they can refer to L amino acid residues. Glycine has no asymmetric carbon atom and is simply referred to as “Gly” or “G”. The amino acid sequences of peptides set forth herein are generally designated using the standard single letter symbol. (A, Alanine; C, Cysteine; D, Aspartic Acid; E, Glutamic Acid; F, Phenylalanine; G, Glycine; H, Histidine; I, Isoleucine; K, Lysine; L, Leucine; M, Methionine; N, Asparagine; P, Proline; Q, Glutamine; R, Arginine; S, Serine; T, Threonine; V, Valine; W, Tryptophan; and Y, Tyrosine.)

[0769] The terms “polynucleotide” and “nucleic acid” are used interchangeably herein and refer to polymers of nucleotides of any length, and include DNA and RNA, for example, mRNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase. In some embodiments, the polynucleotide and nucleic acid can be in vitro transcribed mRNA. In some embodiments, the polynucleotide that is administered is mRNA.

[0770] The terms “identical” or percent “identity” in the context of two or more nucleic acids or polypeptides, refer to two or more sequences or subsequences that are the same or have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned (introducing gaps, if necessary) for maximum correspondence, not considering any conservative amino acid substitutions as part of the sequence identity. The percent identity can be measured using sequence comparison software or algorithms or by visual inspection. Various algorithms and software that can be used to obtain alignments of amino acid or nucleotide sequences are well-known in the art. These include, but are not limited to, BLAST, ALIGN, Megalign, BestFit, GCG Wisconsin Package, and variations thereof. In some embodiments, two nucleic acids or polypeptides described herein are substantially identical, meaning they have at least 70%, at least 75%, at l...

Claims

1-61. (canceled)62. A method of treating or preventing an infection by a virus or treating a respiratory disease or condition associated with an infection by a virus comprising administering to a subject in need thereof a pharmaceutical composition comprising: a polypeptide having an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of any one of the sequences depicted in column 2 of Table 11, column 2 of Table 12 or column 3 of Table 15; or a recombinant polynucleotide encoding a polypeptide having an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence of any one of the sequences depicted in column 2 of Table 11, column 2 of Table 12 or column 3 of Table 15.

63. The method of claim 62, wherein the subject has an immunodeficiency.

64. The method of claim 63, wherein the subject has a B cell immunodeficiency.

65. The method of claim 62, wherein the pharmaceutical composition comprises a polypeptide with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence selected from the group consisting of RS Clp1full, RS C2p1full, RS C3p1full, RS C4p1full, RS C5p1, RS C5p2, RS C5p2full, RS C6p1, RS C6p2, RS C6p2full, RS C7p1, RS C7p2, RS C7p2full, RS C7p4, RS C7p4full, RS C8p1, RS C8p2 and RS C8p2full; or a polynucleotide encoding a polypeptide with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence selected from the group consisting of RS Clp1full, RS C2p1full, RS C3p1full, RS C4p1full, RS C5p1, RS C5p2, RS C5p2full, RS C6p1, RS C6p2, RS C6p2full, RS C7p1, RS C7p2, RS C7p2full, RS C7p4, RS C7p4full, RS C8p1, RS C8p2, and RS C8p2full.

66. The method of claim 62, wherein the pharmaceutical composition comprises a polynucleotide with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: RS C1n1, RS C2n1, RS C3n1, RS C4n1, RS C5n1, RS Con1, RS C7n1, RS C8n1, RS C5n2, RS Con2, RS C7n2, RS C8n2, RS C5n2full, RS Con2full, RS C7n2full, RS C8n2full, RS C7n4, RS C7n4full.

67. The method of claim 62, wherein the polynucleotide is an mRNA.

68. The method of claim 62, wherein the pharmaceutical composition further comprises one or more lipids.

69. The method of claim 68, wherein the one or more lipids comprise a lipid nanoparticle (LNP), and wherein the LNP encapsulates the recombinant polynucleotide construct.71-115. (canceled)116. A pharmaceutical composition comprising:(i) a first recombinant polynucleotide encoding a polypeptide comprising at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and(ii) a second recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof.

117. The pharmaceutical composition of claim 116, wherein the pharmaceutical composition comprises a nanoparticle, wherein the nanoparticle comprises the first recombinant polynucleotide and the second recombinant polynucleotide.

118. The pharmaceutical composition of claim 117, wherein the nanoparticle is present in the pharmaceutical composition at a dose of from 100 ng to 500 micrograms.

119. The pharmaceutical composition of claim 116, wherein the mass ratio of the first recombinant polynucleotide to the second recombinant polynucleotide is from about 1:50 to 50:1.

120. A composition comprising:(i) a first pharmaceutical composition comprising a recombinant polynucleotide encoding a polypeptide comprising at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and(ii) a second pharmaceutical composition comprising a recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof.

121. The composition of claim 120, wherein the first pharmaceutical composition comprises a first nanoparticle, wherein the first nanoparticle comprises the recombinant polynucleotide encoding a polypeptide comprising at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, a sequence comprising an epitope sequence from membrane glycoprotein (M), and a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); and wherein the second pharmaceutical composition comprises a second nanoparticle, wherein the second nanoparticle comprises the recombinant polynucleotide encoding a 2019 SARS-CoV 2 spike protein or a variant or fragment thereof.

122. The composition of claim 121, wherein the mass ratio of the recombinant polynucleotide in (i) to the recombinant polynucleotide in (ii) is from about 1:50 to 50:1.

123. The composition of claim 121, wherein the first nanoparticle is present in the first pharmaceutical composition at a dose of from about 100 ng to 500 micrograms.

124. The composition of claim 121, wherein the second nanoparticle is present in the second pharmaceutical composition at a dose of from about 100 ng to 500 micrograms.

125. The composition of claim 121, wherein the recombinant polynucleotide in (i) is present in the first pharmaceutical composition at a dose of from about 50 ng to 250 micrograms.

126. The composition of claim 121, wherein the recombinant polynucleotide in (ii) is present in the second pharmaceutical composition at a dose of from about 50 ng to 250 micrograms.

127. The composition of claim 121, wherein the nanoparticle is a lipid nanoparticle.128-149. (canceled)

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